Fused pyrrolocarbazoles

ABSTRACT

The present invention relates generally to selected fused pyrrolocarbazoles, including pharmaceutical compositions thereof and methods of treating diseases therewith. The present invention is also directed to intermediates and processes for making these fused pyrrolocarbazoles.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.11/017,915, filed Dec. 22, 2004, now allowed, which in turn claimspriority of U.S. Provisional Application No. 60/532,252, filed Dec. 23,2003. The entire contents of these prior applications are incorporatedby reference herein for all purposes.

FIELD OF THE INVENTION

The present invention relates generally to fused pyrrolocarbazoles,including pharmaceutical compositions, diagnostic kits, assay standardsor reagents containing the same, and methods of using the same astherapeutics. The invention is also directed to intermediates andprocesses for making these novel compounds.

BACKGROUND OF THE INVENTION

Publications cited throughout this disclosure are incorporated in theirentirety herein by reference.

Various synthetic small organic molecules that are biologically activeand generally known in the art as “fused pyrrolocarbazoles” have beenprepared (See U.S. Pat. Nos. 5,475,110; 5,591,855; 5,594,009; 5,616,724;and 6,630,500). In addition, U.S. Pat. No. 5,705,511 discloses fusedpyrrolocarbazole compounds which possess a variety of functionalpharmacological activities. The fused pyrrolocarbazoles were disclosedto be used in a variety of ways, including: enhancing the functionand/or survival of cells of neuronal lineage, either singularly or incombination with neurotrophic factor(s) and/or indolocarbazoles;enhancing trophic factor-induced activity; inhibition of protein kinaseC (“PKC”) activity; inhibition of trk tyrosine kinase activity;inhibition of proliferation of a prostate cancer cell-line; inhibitionof the cellular pathways involved in the inflammation process; andenhancement of the survival of neuronal cells at risk of dying. However,there remains a need for novel pyrrolocarbazole derivatives that possessbeneficial properties. This invention is directed to this, as well asother important ends.

SUMMARY OF THE INVENTION

The present invention in one aspect is directed to fusedpyrrolocarbazole compounds of Formula I:

and its stereoisomeric forms, mixtures of stereoisomeric forms, orpharmaceutically acceptable salt forms thereof, wherein the constituentmembers are defined infra.

The fused pyrrolocarbazoles of the present invention may be used in avariety of ways, including: for inhibition of angiogenesis; as antitumoragents; for enhancing the function and/or survival of cells of neuronallineage, either singularly or in combination with neurotrophic factor(s)and/or indolocarbazoles; for enhancing trophic factor-induced activity;inhibition of kinase activity, such as trk tyrosine kinase (“trk”),vascular endothelial growth factor receptor (“VEGFR”) kinase, preferablyVEGFR1 and VEGFR2, mixed lineage kinase (“MLK”), dual leucine zipperbearing kinase (“DLK”), platelet derived growth factor receptor kinase(“PDGFR”), protein kinase C (“PKC”), Tie-2, or CDK-1, -2, -3, -4, -5,-6; for inhibition of NGF-stimulated trk phosphorylation; for inhibitionof proliferation of a prostate cancer cell-line; for inhibition of thecellular pathways involved in the inflammation process; and forenhancement of the survival of neuronal cells at risk of dying. Inaddition, the fused pyrrolocarbazoles may useful for inhibition ofc-met, c-kit, and mutated Flt-3 containing internal tandem duplicationsin the juxtamembrane domain. Because of these varied activities, thedisclosed compounds find utility in a variety of settings, includingresearch and therapeutic environments.

In other embodiments, the compounds of the present invention are usefulfor treating or preventing angiogenesis and angiogenic disorders such ascancer of solid tumors, endometriosis, retinopathy, diabeticretinopathy, psoriasis, hemangioblastoma, ocular disorders or maculardegeneration. In another embodiment, the compounds of the presentinvention are useful for treating or preventing neoplasia, rheumatoidarthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis,abnormal wound healing, atherosclerosis, or restenosis. In furtherembodiments, the compounds of the present invention are useful fortreating or preventing neurodegenerative diseases and disorders, such asAlzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease,stroke, ischemia, Huntington's disease, AIDS dementia, epilepsy,multiple sclerosis, peripheral neuropathy, chemotherapy inducedperipheral neuropathy, AIDS related peripheral neuropathy, or injuriesof the brain or spinal chord. In additional embodiments, the compoundsof the present invention are useful for treating or preventing prostatedisorders such as prostate cancer or benign prostate hyperplasia. Instill other embodiments, the compounds of the present invention areuseful for treating or preventing multiple myeloma and leukemiasincluding, but not limited to, acute myelogenous leukemia, chronicmyelogenous leukemia, acute lymphocytic leukemia, and chroniclymphocytic leukemia.

In further aspect, the present invention is directed to pharmaceuticalcompositions which comprises one or more pharmaceutically acceptableexcipients and a therapeutically effective amount of a compound of thepresent invention.

DETAILED DESCRIPTION

Thus, in a first embodiment, the present invention provides a novelcompound of Formula I:

wherein:

-   -   ring A together with the carbon atoms to which it is attached,        is selected from:        -   (a) a phenylene ring in which from 1 to 3 carbon atoms may            be replaced by nitrogen atoms; and        -   (b) a 5-membered aromatic ring in which from 1 to 2 carbon            atoms may be replaced by nitrogen atoms;    -   A¹ and A² are independently selected from H, H; and a group        wherein A¹ and A² together form a moiety selected from ═O;    -   B¹ and B² are independently selected from H, H; and a group        wherein B¹ and B² together form a moiety selected from ═O;    -   provided that at least one of the pairs A¹ and A², or B¹ and B²        forms ═O;    -   R¹ is H or optionally substituted alkyl, wherein said optional        substituents are one to three R¹⁰ groups;    -   R² is selected from H, C(═O)R^(2a), C(═O)NR^(2c)R^(2d),        SO₂R^(2b), CO₂R^(2b), optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl, optionally        substituted cycloalkyl, and optionally substituted        heterocycloalkyl, wherein said optional substituents are one to        three R¹⁰ groups;    -   R^(2a) is selected from optionally substituted alkyl, optionally        substituted aryl, OR^(2b), NR^(2c)R^(2d),        (CH₂)_(p)NR^(2c)R^(2d), and O(CH₂)_(p)NR^(2c)R^(2d), wherein        said optional substituents are one to three R¹⁰ groups;    -   R^(2b) is selected from H and optionally substituted alkyl,        wherein said optional substituents are one to three R¹⁰ groups;    -   R^(2c) and R^(2d) are each independently selected from H and        optionally substituted alkyl, or together with the nitrogen to        which they are attached form an optionally substituted        heterocycloalkyl, wherein said optional substituents are one to        three R¹⁰ groups;    -   at least one of R³, R⁴, R⁵, and R⁶ is selected from OR¹⁴;        C(═O)R²²; CH═NR²⁶; NR¹¹C(═O)R²⁰; NR¹¹C(═O)OR¹⁵; OC(═O)R²⁰;        OC(═O)NR¹¹R²⁰; O-(alkylene)-R²⁴; Z¹-(alkylene)-R²³, wherein Z¹        is selected from CO₂, O₂C, C(═O), NR¹¹, NR¹¹C(═O), and        NR¹¹C(═O)O; and (alkylene)-Z²-(alkylene)-R²³, wherein Z² is        selected from O, S(O)_(y), C(═O)NR¹¹, NR¹¹C(═O), NR¹¹C(═O)NR¹¹,        OC(═O)NR¹¹, NR¹¹C(═O)O;        -   wherein said alkylene groups are optionally substituted with            one to three R¹⁰ groups;    -   the other R³, R⁴, R⁵, or R⁶ moieties can be selected        independently from H, R¹⁰, optionally substituted alkyl,        optionally substituted alkenyl, and optionally substituted        alkynyl, wherein said optional substituents are one to three R¹⁰        groups;    -   Q is selected from an optionally substituted C₁₋₂ alkylene,        wherein said optional substituents are one to three R¹⁰ groups;    -   R¹⁰ is selected from alkyl, cycloalkyl, spirocycloalkyl, aryl,        heteroaryl, heterocycloalkyl, arylalkoxy, F, Cl, Br, I, CN, CF₃,        NR^(27A)R^(27B), NO₂, OR²⁵, OCF₃, ═O, ═NR²⁵, ═N—OR²⁵,        ═N—N(R²⁵)₂, OC(═O)R²⁵, OC(═O)NHR¹¹, O—Si(R¹⁶)₄,        O-tetrahydropyranyl, ethylene oxide, NR¹⁶C(═O)R²⁵, NR¹⁶CO₂R²⁵,        NR¹⁶C(═O)NR^(27A)R^(27B), NHC(═NH)NH₂, NR¹⁶S(O)₂R²⁵,        S(O)_(y)R²⁵, CO₂R²⁵, C(═O)NR^(27A)R^(27B), C(═O)R²⁵, CH₂OR²⁵,        (CH₂)_(p)OR²⁵, CH═NNR^(27A)R^(27B), CH═NOR²⁵, CH═NR²⁵,        CH═NNHCH(N═NH)NH₂, S(═O)₂NR^(27A)R^(27B), P(═O)(OR²⁵)₂, OR¹³,        and a monosaccharide wherein each hydroxyl group of the        monosaccharide is independently either unsubstituted or is        replaced by H, alkyl, alkylcarbonyloxy, or alkoxy;    -   R¹¹ is selected from H and optionally substituted alkyl, wherein        said optional substituents are one to three R¹⁰ groups;    -   R¹² is selected from optionally substituted alkyl, optionally        substituted aryl, and optionally substituted heteroaryl, wherein        said optional substituents are one to three R¹⁰ groups;    -   R¹³ is the residue of an amino acid after the removal of the        hydroxyl moeity from the carboxyl group thereof;    -   R¹⁴ is optionally substituted heteroaryl, wherein said optional        substituents is one to three R¹⁰ groups;    -   R¹⁵ is optionally substituted alkyl, wherein said optional        substituents is one to three R¹⁰ groups;    -   R¹⁶ is H or alkyl;    -   R¹⁷ is selected from optionally substituted alkyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted cycloalkyl, and optionally substituted        heterocycloalkyl, wherein said optional substituents are one to        three R¹⁰ groups;    -   R¹⁸ is selected from H, optionally substituted alkyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted cycloalkyl, and optionally substituted        heterocycloalkyl, wherein said optional substituents are one to        three R¹⁰ groups;    -   R¹⁹ is selected from optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, and optionally        substituted heteroaryl, wherein said optional substituents are        one to three R¹⁰ groups;    -   R²⁰ is selected from optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted cycloalkyl, and        optionally substituted heterocycloalkyl, wherein said optional        substituents are one to three R¹⁰ groups;    -   R²¹ is selected from H, optionally substituted alkyl, optionally        substituted alkenyl, optionally substituted alkynyl, optionally        substituted aryl, optionally substituted arylalkyl, optionally        substituted heteroaryl, optionally substituted cycloalkyl, and        optionally substituted heterocycloalkyl, wherein said optional        substituents are one to three R¹⁰ groups;    -   R²² is selected from optionally substituted aryl, and optionally        substituted heteroaryl, wherein said optional substituents are        one to three R¹⁰ groups;    -   R²³ is selected from optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted cycloalkyl,        optionally substituted heterocycloalkyl, OR²¹, O(CH₂)_(p)OR²¹,        (CH₂)_(p)OR²¹, SR¹⁸, SOR¹⁷, SO₂R¹⁸, CN, N(R²⁰)₂,        CHOH(CH₂)_(p)N(R¹¹)₂, C(═O)N(R¹⁸)₂, NR¹⁸C(═O)R¹⁸,        NR¹⁸C(═O)N(R¹⁸)₂, C(═NR¹⁸)OR¹⁸, C(R¹²)═NOR¹⁸, NHOR²¹,        NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, NHCN, CONR¹⁸OR¹⁸, CO₂R¹⁸, OCOR¹⁷,        OC(═O)N(R¹⁸)₂, NR¹⁸C(═O)OR¹⁷, and C(═O)R¹⁸, wherein said        optional substituents are one to three R¹⁰ groups;    -   R²⁴ is selected from optionally substituted alkenyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted cycloalkyl, optionally substituted heterocycloalkyl,        CN, OR²¹, O(CH₂)_(p)OR²¹, (CH₂)_(p)OR²¹, SR¹⁹, SOR¹⁷, SO₂R¹⁸,        N(R¹⁸)₂, CHOH(CH₂)_(p)N(R¹¹)₂, NR¹⁸C(═O)R¹⁸, NR¹⁸C(═O)N(R¹⁸)₂,        C(═NR¹⁸)OR¹⁸, NHOR²¹, NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, NHCN, C(═O)N(R¹⁸)₂,        C(═O)NR^(27A)R^(27B), C(═O)NR¹¹R²⁸, C(═O)NR¹⁸OR¹⁸,        C(═O)NR¹¹N(R¹¹)₂, C(═O)NR¹¹(alkylene)NR^(27A)R^(27B), CO₂R¹⁸,        OCOR¹⁷, OC(═O)N(R¹⁸)₂, NR¹⁸C(═O)OR¹⁷, C(═O)NR¹¹R¹⁸ and C(═O)R¹⁸,        wherein said optional substituents are one to three R¹⁰ groups;    -   R²⁵ is H, alkyl, aryl, heteroaryl, cycloalkyl, or        heterocycloalkyl;    -   R²⁶ is selected from optionally substituted cycloalkyl and        optionally substituted heterocycloalkyl, wherein said optional        substituents are one to three R¹⁰ groups;    -   R^(27A) and R^(27B) are each independently selected from H and        alkyl, or together with the nitrogen to which they are attached        form an optionally substituted heterocycloalkyl, wherein said        optional substituents are selected from alkyl, aryl and        heteroaryl;    -   R²⁸ is optionally substituted arylalkyl, wherein said optional        substituent is one to three R¹⁰ groups;    -   p is independently selected from 1, 2, 3, and 4;    -   y is independently selected from 0, 1 and 2; and    -   a stereoisomer or a pharmaceutically acceptable salt form        thereof.

In another embodiment, the compounds of Formula I as defined herein arenot intended to include any compounds disclosed in PCT Publ. No. WO98/07433. In particular, when A¹,A² is ═O; B¹, B² are independently H orOH, or B¹, B² combine to form ═O; rings A and B are each phenylene; Q isCH—R^(a); and one of R² or R^(a) is H and the other is optionallysubstituted

wherein W is optionally substituted C₁ alkyl, or NR^(27A)R^(27B); thenany of R³, R⁴, R⁵, and R⁶ cannot include OR¹⁴ or O-(alkylene)-R²⁴.

Other aspects of the present invention include the compounds of FormulaI as defined herein wherein ring A is phenylene; or a 5-memberedaromatic ring containing one nitrogen atom, preferably pyrazolylene, andmore preferably

Further aspects include those compounds wherein R¹ is H or optionallysubstituted alkyl. Another aspect includes those compounds wherein R² isH, C(═O)R^(2a), C(═O)NR^(2c)R^(2d), SO₂R^(2b), CO₂R^(2b), optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, or optionally substituted cycloalkyl, andpreferably H, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, or optionally substitutedcycloalkyl, and more preferably R² is H or optionally substituted alkyl.Additional aspects include those compounds wherein groups A¹A² are H, H;and B¹B² together form ═O. In yet another aspect, the invention includescompounds wherein Q is selected from an optionally substituted C₁₋₂alkylene, or preferably Q is CH₂, or CH₂CH₂. Further aspects includethose compounds wherein R¹⁴ is benzoxazole, benzothiazole, pyrimidine,pyrazine or triazine; R²² is a 5-membered heteroaryl group; R²⁰ isheterocycloalkyl or heteroaryl; R²³ is heteroaryl or heterocycloalkyl;R²⁴ is heteroaryl; and R²⁶ is heterocycloalkyl. Additional aspects ofthe present invention include any combination of the above preferredsubstituents, such as, for example, a compound of Formula I with thepreferred moieties of groups R¹ and R²; or R¹ and Q; or R¹, R²; or Q;etc.

In another embodiment of the present invention, there are includedcompounds having a structure of Formula II:

In one aspect, there are included compounds of Formula II wherein ring Ais phenylene or pyrazolylene, preferably

Another aspect includes those compounds wherein R¹ is H or optionallysubstituted alkyl. Further aspects include those compounds wherein R² isH, C(═O)R^(2a), C(═O)NR^(2c)R^(2d), SO₂R^(2b), CO₂R^(2b), optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, or optionally substituted cycloalkyl, andpreferably H, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, or optionally substitutedcycloalkyl, and more preferably R² is H or optionally substituted alkyl.Additional aspects include compounds wherein Q is selected from anoptionally substituted C₁₋₂ alkylene, or preferably Q is CH₂ or CH₂CH₂.Additional aspects of the present invention include any combination ofthe above preferred substituents, such as, for example, a compound ofFormula II with the preferred moieties of groups R¹ and R²; or R¹ and Q;or R¹, R²; or Q; etc.

In yet another embodiment of the present invention, there are includedcompounds having a structure of Formula III:

where preferrably ring A is phenylene or pyrazolylene, preferably

and R¹ is H or optionally substituted alkyl; and Formula IV:

and Formula V:

and Formula VI:

In certain aspects of the present invention, there are includedcompounds of Formulas III-VI wherein R² is H, C(═O)R^(2a),C(═O)NR^(2c)R^(2d), SO₂R^(2b), CO₂R^(2b), optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl, oroptionally substituted cycloalkyl, and preferably H, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, or optionally substituted cycloalkyl, and morepreferably R² is H or optionally substituted alkyl. Other aspectsinclude those compounds wherein Q is selected from an optionallysubstituted C₁₋₂ alkylene, or preferably Q is CH₂ or CH₂CH₂. Additionalaspects of the present invention include any combination of the abovepreferred substituents for each of Formulas III-VI.

The following paragraphs show additional aspects of the invention for atleast one R³, R⁴, R⁵, and R⁶ for compounds of Formulas I-VI and theirrespective preferred embodiments described heretofore.

-   -   1. OR¹⁴; particularly those wherein R¹⁴ is optionally        substituted benzoxazole, optionally substituted benzothiazole,        optionally substituted pyrimidine, optionally substituted        pyrazine or optionally substituted triazine.    -   2. C(═O)R²²; particularly those wherein R²² is an optionally        substituted 5-membered heteroaryl group.    -   3. CH═NR²⁶; particularly those wherein R²⁶ is optionally        substituted heterocycloalkyl.    -   4. NR¹¹C(═O)R²⁰; particularly those wherein R²⁰ is optionally        substituted heteroaryl.    -   5. NR¹¹C(═O)OR¹⁵.    -   6. OC(═O)R²⁰; particularly those wherein R²⁰ is optionally        substituted heterocycloalkyl.    -   7. OC(═O)NR¹¹R²⁰; particularly those wherein R²⁰ is optionally        substituted cycloalkyl or optionally substituted        heterocycloalkyl.    -   8. O-(alkylene)-R²⁴; particularly those wherein R²⁴ is        optionally substituted heterocycloalkyl    -   9. Z¹-(alkylene)-R²³, wherein Z¹ is selected from CO₂, O₂C,        C(═O), NR¹¹, NR¹¹C(═O), and NR¹¹C(═O)O; particularly those        wherein Z¹ is C(═O) or NR¹¹.    -   10. (alkylene)-Z²-(alkylene)-R²³, wherein Z² is selected from O,        S(O)_(y), C(═O)NR¹¹, NR¹¹C(═O), NR¹¹C(═O)NR¹¹, OC(═O)NR¹¹,        NR¹¹C(═O)O; particularly those wherein Z² is O, C(═O)NR¹¹, or        NR¹¹C(═O).

The preceding paragraphs may be combined to further define additionalpreferred embodiments of compounds of Formulas I-VI. For example, onesuch combination for R³, R⁴, R⁵, or R⁶ can include OR¹⁴; C(═O)R²²;NR¹¹C(═O)R²⁰; NR¹¹C(═O)OR¹⁵; OC(═O)R²⁰; or OC(═O)NR¹¹R²⁰.

Another such combination includes OR¹⁴; C(═O)R²²; and NR¹¹C(═O)OR¹⁵.

A third such combination includes OR¹⁴, wherein R¹⁴ is benzoxazole,benzothiazole, pyrimidine, pyrazine or triazine; C(═O)R²², wherein R²²is a 5-membered heteroaryl group; NR¹¹C(═O)R²⁰, wherein R²⁰ isheteroaryl; NR¹¹C(═O)OR¹⁵; OC(═O)R²⁰, wherein R²⁰ is heterocycloalkyl;or OC(═O)NR¹¹R²⁰, wherein R²⁰ is cycloalkyl, wherein each R¹⁴, R²², andR²⁰ is optionally substituted as set forth above.

The following terms and expressions used herein have the indicatedmeanings.

In the formulas described and claimed herein, it is intended that whenany symbol appears more than once in a particular formula orsubstituent, its meaning in each instance is independent of the other.

As used herein, the term “about” refers to a range of values from ±10%of a specified value. For example, the phrase “about 50 mg” includes±10% of 50, or from 45 to 55 mg.

As used herein, a range of values in the form “x-y” or “x to y”, or “xthrough y”, include integers x, y, and the integers therebetween. Forexample, the phrases “1-6”, or “1 to 6” or “1 through 6” are intended toinclude the integers 1, 2, 3, 4, 5, and 6. Preferred embodiments includeeach individual integer in the range, as well as any subcombination ofintegers. For example, preferred integers for “1-6” can include 1, 2, 3,4, 5, 6, 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 2-6, etc.

As used herein “stable compound” or “stable structure” refers to acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and preferably capable offormulation into an efficacious therapeutic agent. The present inventionis directed only to stable compounds.

As used herein, the term “alkyl” refers to a straight-chain, or branchedalkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, hexyl, octyl, etc. The alkyl moiety ofalkyl-containing groups, such as alkoxy, alkoxycarbonyl, andalkylaminocarbonyl groups, has the same meaning as alkyl defined above.Lower alkyl groups, which are preferred, are alkyl groups as definedabove which contain 1 to 4 carbons. A designation such as “C₁-C₄ alkyl”refers to an alkyl radical containing from 1 to 4 carbon atoms.

As used herein, the term “alkenyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon-carbon double bond. A designation “C₂-C₈ alkenyl” refers to analkenyl radical containing from 2 to 8 carbon atoms. Examples of alkenylgroups include ethenyl, propenyl, isopropenyl, 2,4-pentadienyl, etc.

As used herein, the term “alkynyl” refers to a straight chain, orbranched hydrocarbon chains of 2 to 8 carbon atoms having at least onecarbon-carbon triple bond. A designation “C₂-C₈ alkynyl” refers to analkynyl radical containing from 2 to 8 carbon atoms. Examples includeethynyl, propynyl, isopropynyl, 3,5-hexadiynyl, etc.

As used herein, the term “alkylene” refers to a branched or straightchained hydrocarbon of 1 to 8 carbon atoms, which is formed by theremoval of two hydrogen atoms. A designation such as “C₁-C₄ alkylene”refers to an alkylene radical containing from 1 to 4 carbon atoms.Examples include methylene (—CH₂—), propylidene (CH₃CH₂CH═),1,2-ethandiyl (—CH₂CH₂—), etc.

As used herein, the term “phenylene” refers to a phenyl group with anadditional hydrogen atom removed, ie. a moiety with the structure of:

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated mono- or bicyclic alkyl ring system containing 3 to 10 carbonatoms. A designation such as “C₅-C₇ cycloalkyl” refers to a cycloalkylradical containing from 5 to 7 ring carbon atoms. Preferred cycloalkylgroups include those containing 5 or 6 ring carbon atoms. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, etc.

As used herein, the term “spirocycloalkyl” refers to a cycloalkyl groupbonded to a carbon chain or carbon ring moiety by a carbon atom commonto the cycloalkyl group and the carbon chain or carbon ring moiety. Forexample, a C₃ alkyl group substituted with an R group wherein the Rgroup is spirocycloalkyl containing 5 carbon atoms refers to:

As used herein, the term “aryl” refers to a mono- or bicyclichydrocarbon aromatic ring system having 6 to 12 ring carbon atoms.Examples include phenyl and naphthyl. Preferred aryl groups includephenyl or naphthyl groups. Included within the definition of “aryl” arefused ring systems, including, for example, ring systems in which anaromatic ring is fused to a cycloalkyl ring. Examples of such fused ringsystems include, for example, indane and indene.

As used herein, the terms “heterocycle”, “heterocyclic” or“heterocyclyl” refer to a mono- di-, tri- or other multicyclic aliphaticring system that includes at least one heteroatom such as O, N, or S.The nitrogen and sulfur heteroatoms may be optionally oxidized, and thenitrogen may be optionally substituted in non-aromatic rings.Heterocycles are intended to include heteroaryl and heterocycloalkylgroups.

Some heterocyclic groups containing one or more nitrogen atoms includepyrrolidine, pyrroline, pyrazoline, piperidine, morpholine,thiomorpholine, N-methylpiperazine, indole, isoindole, imidazole,imidazoline, oxazoline, oxazole, triazole, thiazoline, thiazole,isothiazole, thiadiazole, triazine, isoxazole, oxindole, pyrazole,pyrazolone, pyrimidine, pyrazine, quinoline, iosquinoline, and tetrazolegroups. Some heterocyclic groups formed containing one or more oxygenatoms include furan, tetrahydrofuran, pyran, benzofurans,isobenzofurans, and tetrahydropyran groups. Some heterocyclic groupscontaining one or more sulfur atoms include thiophene, thianaphthene,tetrahydrothiophene, tetrahydrothiapyran, and benzothiophenes.

As used herein, the term “heterocycloalkyl” refers to a cycloalkyl groupin which one or more ring carbon atoms are replaced by at least onehetero atom such as —O—, —N—, or —S—, and includes ring systems whichcontain a saturated ring group bridged or fused to one or more aromaticgroups. Some heterocycloalkyl groups containing both saturated andaromatic rings include phthalamide, phthalic anhydride, indoline,isoindoline, tetrahydroisoquinoline, chroman, isochroman, and chromene.

As used herein, the term “heteroaryl” refers to an aryl group containing5 to 10 ring carbon atoms in which one or more ring carbon atoms arereplaced by at least one hetero atom such as —O—, —N—, or —S—. Someheteroaryl groups of the present invention include pyridyl, pyrimidyl,purinyl, pyrrolyl, pyridazinyl, pyrazinyl, triazinyl, imidazolyl,triazolyl, tetrazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl,qunioxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzoimidazolyl,pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl, isoxazolyl,naphthyridinyl, oxindolyl, and benzothiazolyl groups.

As used herein, the term “arylalkyl” refers to an alkyl group that issubstituted with an aryl group. Examples of arylalkyl groups include,but are not limited to, benzyl, phenethyl, benzhydryl, diphenylmethyl,triphenylmethyl, diphenylethyl, naphthylmethyl, etc.

As used herein, the term “arylalkoxy” refers to an aryl-substitutedalkoxy group, such as benzyloxy, diphenylmethoxy, triphenylmethoxy,phenylethoxy, diphenylethoxy, etc.

As used herein, the term “monosaccharide” refers to a simple sugar ofthe formula (CH₂O)_(n). The monosaccharides can be straight-chain orring systems, and can include a saccharose unit of the formula—CH(OH)—C(═O)—. Examples of monosaccharides include erythrose, threose,ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose,gulose, idose, galactose, talose, erythulose, ribulose, xyulose,psicose, fructose, sorbose, tagatose, erythropentulose, threopentulose,glycerotetrulose, glucopyranose, fructofuranose, etc.

As used herein, the term “amino acid” refers to a group containing bothan amino group and a carboxyl group. Embodiments of amino acids includeα-amino, β-amino, γ-amino acids. The α-amino acids have a generalformula HOOC—CH(side chain)—NH₂. The amino acids can be in their D, L orracemic configurations. Amino acids include naturally-occurring andnon-naturally occurring moieties. The naturally-occurring amino acidsinclude the standard 20 α-amino acids found in proteins, such asglycine, serine, tyrosine, proline, histidine, glutamine, etc.Naturally-occurring amino acids can also include non-α-amino acids (suchas β-alanine, γ-aminobutyric acid, homocysteine, etc.), rare amino acids(such as 4-hydroxyproline, 5-hydroxylysine, 3-methylhistidine, etc.) andnon-protein amino acids (such as citrulline, ornithine, canavanine,etc.). Non-naturally occurring amino acids are well-known in the art,and include analogs of natural amino acids. See Lehninger, A. L.Biochemistry, 2^(nd) ed.; Worth Publishers: New York, 1975; 71-77, thedisclosure of which is incorporated herein by reference. Non-naturallyoccurring amino acids also include α-amino acids wherein the side chainsare replaced with synthetic derivatives. In certain embodiments,substituent groups for the compounds of the present invention includethe residue of an amino acid after removal of the hydroxyl moiety of thecarboxyl group thereof; i.e., groups of formula —C(═O)CH(sidechain)—NH₂. Representative side chains of naturally occurring andnon-naturally occurring α-amino acids include are shown below in TableA.

TABLE A H HS—CH₂— CH₃— HO₂C—CH(NH₂)—CH₂—S—S—CH₂— HO—CH₂— CH₃—CH₂—C₆H₅—CH₂— CH₃—S—CH₂—CH₂— HO—C₆H₄—CH₂— CH₃—CH₂—S—CH₂—CH₂—

HO—CH₂—CH₂—C₅H₉—C₆H₁₁—C₆H₁₁—CH₂—CH₃—CH(OH)—

HO₂C—CH₂—NHC(═O)—CH₂—HO₂C—CH₂—HO₂C—CH₂—CH₂—NH₂C(═O)—CH₂—

NH₂C(═O)—CH₂—CH₂—(CH₃)₂—CH—(CH₃)₂—CH—CH₂—CH₃—CH₂—CH₂—

H₂N—CH₂—CH₂—CH₂—H₂N—C(═NH)—NH—CH₂—CH₂—CH₂—H₂N—C(═O)—NH—CH₂—CH₂—CH₂—

CH₃—CH₂—CH(CH₃)—CH₃—CH₂—CH₂—CH₂—H₂N—CH₂—CH₂—CH₂—CH₂—

As used herein, the term “trk” refers to the family of high affinityneurotrophin receptors presently comprising trk A, trk B, and trk C, andother membrane associated proteins to which a neurotrophin can bind.

As used herein, the term “VEGFR” refers to the family of high affinityvascular endothelial growth factor receptors presently comprisingVEGFR1, VEGFR2, VEGFR3, and other membrane associated proteins to whicha VEGF can bind.

As used herein, the term “MLK” refers to the family of high affinitymixed lineage kinases presently comprising MLK1, MLK2, MLK3, MLK4α & β,DLK, LZK, ZAK α & β, and other serine/threonine kinases classifiedwithin this family.

As used herein, the terms “enhance” or “enhancing” when used to modifythe terms “function” or “survival” means that the presence of a compoundof the present invention has a positive effect on the function and/orsurvival of a trophic factor responsive cell compared with a cell in theabsence of the compound. For example, and not by way of limitation, withrespect to the survival of, e.g., a cholinergic neuron, a compound ofthe present invention would evidence enhancement of survival of acholinergic neuronal population at risk of dying (due to, e.g., injury,a disease condition, a degenerative condition or natural progression)when compared to a cholinergic neuronal population not presented withsuch a compound, if the treated population has a comparatively greaterperiod of functionality than the non-treated population. As a furtherexample, and again not by way of limitation, with respect to thefunction of, e.g., a sensory neuron, a compound of the present inventionwould evidence enhancement of the function (e.g. neurite extension) of asensory neuronal population when compared to a sensory neuronalpopulation not presented with such a compound, if the neurite extensionof the treated population is comparatively greater than the neuriteextension of the non-treated population.

As used herein, the terms “inhibit” or “inhibition” refer to a specifiedresponse of a designated material (e.g., enzymatic activity) iscomparatively decreased in the presence of a compound of the presentinvention.

As used herein, the terms “cancer” or “cancerous” refer to any malignantproliferation of cells in a mammal. Examples include prostate, benignprostate hyperplasia, ovarian, breast, brain, lung, pancreatic,colorectal, gastric, stomach, solid tumors, head and neck,neuroblastoma, renal cell carcinoma, lymphoma, leukemia, otherrecognized malignancies of the hematopoietic systems, and otherrecognized cancers.

As used herein the terms “neuron”, “cell of neuronal lineage” and“neuronal cell” refer to a heterogeneous population of neuronal typeshaving singular or multiple transmitters and/or singular or multiplefunctions; preferably, these are cholinergic and sensory neurons. Asused herein, the phrase “cholinergic neuron” means neurons of theCentral Nervous System (CNS) and Peripheral Nervous System (PNS) whoseneurotransmitter is acetylcholine; exemplary are basal forebrain andspinal cord neurons. As used herein, the phrase “sensory neuron”includes neurons responsive to environmental cues (e.g., temperature,movement) from, e.g., skin, muscle and joints; exemplary is a neuronfrom the DRG.

As used herein the term “trophic factor” refers to a molecule thatdirectly or indirectly affects the survival or function of a trophicfactor responsive cell. Exemplary trophic factors include CiliaryNeurotrophic Factor (CNTF), basic Fibroblast Growth Factor (bFGF),insulin and insulin-like growth factors (e.g., IGF-I, IGF-II, IGF-III),interferons, interleukins, cytokines, and the neurotrophins, includingNerve Growth Factor (NGF), Neurotrophin-3 (NT-3), Neurotrophin-4/5(NT-4/5) and Brain Derived Neurotrophic Factor (BDNF).

As used herein the term “trophic factor-responsive cell” refers to acell which includes a receptor to which a trophic factor canspecifically bind; examples include neurons (e.g., cholinergic andsensory neurons) and non-neuronal cells (e.g., monocytes and neoplasticcells).

As used herein the terms “trophic factor activity” and “trophicfactor-induced activity”, refer to both endogenous and exogenous trophicfactors, where “endogenous” refers to a trophic factor normally presentand “exogenous” refers to a trophic factor added to a system. Asdefined, “trophic factor induced activity” includes activity induced by(1) endogenous trophic factors; (2) exogenous trophic factors; and (3) acombination of endogenous and exogenous trophic factors.

As used herein, the term “at risk of dying” in conjunction with abiological material, e.g., a cell such as a neuron, refers to a state orcondition which negatively impacts the biological material such that thematerial has an increased likelihood of dying due to such state orcondition. For example, compounds disclosed herein can “rescue” orenhance the survival of motoneurons which are naturally at risk of dyingin an in ovo model of programmed cell death. Similarly, for example, aneuron may be at risk of dying due to the natural aging process whichoccasions the death of a neuron, or due to an injury, such as a traumato the head, which may be such that neurons and/or glia, for example,impacted by such trauma may be at risk of dying. Further, for example, aneuron may be at risk of dying due to a disease state or condition, asin the case of neurons at risk of dying as occasioned by the diseaseALS. Thus, by enhancing the survival of a cell at risk of dying by useof a compound of the claimed invention is meant that such compounddecreases or prevents the risk of the death of the cell.

As used herein the term “contacting” refers to directly or indirectlycausing placement together of moieties, such that the moieties directlyor indirectly come into physical association with each other, whereby adesired outcome is achieved. Thus, as used herein, one can “contact” atarget cell with a compound as disclosed herein even though the compoundand cell do not necessarily physically join together (as, for example,is the case where a ligand and a receptor physically join together), aslong as the desired outcome is achieved (e.g., enhancement of thesurvival of the cell). Contacting thus includes acts such as placingmoieties together in a container (e.g., adding a compound as disclosedherein to a container comprising cells for in vitro studies) as well asadministration of the compound to a target entity (e.g., injecting acompound as disclosed herein into a laboratory animal for in vivotesting, or into a human for therapy or treatment purposes).

As used herein, a “therapeutically effective amount” refers to an amountof a compound of the present invention effective to prevent or treat thesymptoms of a particular disorder.

As used herein, the term “subject” refers to a warm blooded animal suchas a mammal, preferably a human, or a human child, which is afflictedwith, or has the potential to be afflicted with one or more diseases andconditions described herein.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can beprepared from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two. Generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

As used herein, the term “unit dose” refers to a single dose which iscapable of being administered to a patient, and which can be readilyhandled and packaged, remaining as a physically and chemically stableunit dose comprising either the active compound itself, or as apharmaceutically acceptable composition, as described hereinafter.

As used herein, “prodrug” is intended to include any covalently bondedcarriers which release the active parent compound as defined in thepresent invention in vivo when such prodrug is administered to amammalian subject. Since prodrugs are known to enhance numerousdesirable qualities of pharmaceuticals (e.g., solubility,bioavailability, manufacturing, etc.) the compounds of the presentinvention may be delivered in prodrug form. Thus, the present inventioncontemplates prodrugs of the claimed compounds, compositions containingthe same, and methods of delivering the same. Prodrugs of a compound ofthe present invention may be prepared by modifying functional groupspresent in the compound in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound. Accordingly, prodrugs include, for example, compounds of thepresent invention wherein a hydroxy, amino, or carboxy group is bondedto any group that, when the prodrug is administered to a mammaliansubject, cleaves to form a free hydroxyl, free amino, or carboxylicacid, respectively. Examples include, but are not limited to, acetate,formate and benzoate derivatives of alcohol and amine functional groups;and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl,ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like.

It is recognized that compounds of the present invention may exist invarious stereoisomeric forms. As such, the compounds of the presentinvention include their respective diastereomers or enantiomers. Thecompounds are normally prepared as racemates and can conveniently beused as such, but individual diastereomers or enantiomers can beisolated or synthesized by conventional techniques if so desired. Suchracemates and individual diastereomers or enantiomers and mixturesthereof form part of the present invention.

It is well known in the art how to prepare and isolate such opticallyactive forms. Specific stereoisomers can be prepared by stereospecificsynthesis using enantiomerically pure or enantiomerically enrichedstarting materials. The specific stereoisomers of either startingmaterials or products can be resolved and recovered by techniques knownin the art, such as resolution of racemic forms, normal, reverse-phase,and chiral chromatography, recrystallization, enzymatic resolution, orfractional recrystallization of addition salts formed by reagents usedfor that purpose. Useful methods of resolving and recovering specificstereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry ofOrganic Compounds; Wiley: New York, 1994, and Jacques, J, et al.Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, eachincorporated by reference herein in their entireties.

It is further recognized that functional groups present on the compoundsof the present invention may contain protecting groups. For example, theamino acid side chain substituents of the compounds of the presentinvention can be substituted with protecting groups such asbenzyloxycarbonyl or t-butoxycarbonyl groups. Protecting groups areknown per se as chemical functional groups that can be selectivelyappended to and removed from functionalities, such as hydroxyl groupsand carboxyl groups. These groups are present in a chemical compound torender such functionality inert to chemical reaction conditions to whichthe compound is exposed. Any of a variety of protecting groups may beemployed with the present invention. Preferred groups for protectinglactams include silyl groups such as t-butyldimethylsilyl (“TBDMS”),dimethoxybenzhydryl (“DMB”), acyl, benzyl, and methoxybenzyl groups.Preferred groups for protecting hydroxy groups include TBS, acyl, benzyl(“Bn”), benzyloxycarbonyl (“CBZ”), t-butyloxycarbonyl (“Boc”), andmethoxymethyl. Many other standard protecting groups employed by oneskilled in the art can be found in Greene, T. W. and Wuts, P. G. M.,“Protective Groups in Organic Synthesis” 2d. Ed., Wiley & Sons, 1991.

Synthesis

The general routes to prepare the examples shown in Tables 1-3 of thepresent invention are shown in the Schemes 1-4. The intermediates usedto prepare the examples and their mass spectral data are shown in theTable B. The reagents and starting materials are commercially available,or readily synthesized by well-known techniques by one of ordinary skillin the arts. All processes disclosed in association with the presentinvention are contemplated to be practiced on any scale, includingmilligram, gram, multigram, kilogram, multikilogram or commercialindustrial scale. All substituents in the synthetic schemes, unlessotherwise indicated, are as previously defined.

TABLE B I-14399 (M + 1)

I-18383 (M − 1)

I-19339 (M − 1)

I-22504 (M + 1)

I-23

R 357 (M + 1) 23-1: Ethyl 371 (M + 1) 23-2: nPropyl 385 (M + 1) 23-3:i-butyl 369 (M + 1) 23-4: allyl 426 (M + 1) 23-5: CH₂CH₂NC₄H₈ 400(M + 1) 23-6: CH₂CH₂NMe₂ 482 (M + 1) 23-7: (CH₂)₆NC₄H₈ I-29

R 386 (M + 1) 29-1: i-Propyl 386 (M + 1) 29-2: nPropyl 400 (M + 1) 29-3:i-Butyl 400 (M + 1) 29-4: nButyl I-33

R 373 (M + 1) 33-1: Ethyl 401 (M + 1) 33-2: i-Butyl 387 (M + 1) 33-3:i-Propyl 387 (M + 1) 33-4: Propyl I-36385 (M + 1)

I-39401 (M + 1)

I-41399 (M + 1)

The general procedures to prepare the pyrrolocarbazoles of the presentinvention are described in U.S. Pat. No. 5,705,511 (“the '511 patent”)and U.S. Pat. No. 6,630,500, PCT Publ. No. WO 00/47583, J. HeterocyclicChemistry, 2001, 38, 591, and J. Heterocyclic Chemistry, 2003, 40, 135.In general, the lactam nitrogen or intermediate alcohol groups of theintermediates outlined in Table B may be protected with such groups asacetyl, substituted silyl, benzyl, Boc, or dimethoxybenzhydrol.

Intermediate I-23 (wherein R is hydrogen) used to prepare examples inTable 2, was prepared from the β-ketone,2-methyl-1,4,6,7-tetrahydro-5H-indazol-5-one (Peet, N. P.; LeTourneau,M. E.; Heterocycles, 1991, 32, 41) using methods described in the '511patent and in J. Heterocyclic Chemistry, 2003, 40, 135.

As shown in Scheme 1, the N1-methylpyrazole derivatives in Table 3 wereprepared from the 1-methyl α-ketone (J. Chem. Res., 1986, 1401). TheN2-methyl pyrazole intermediates were prepared according to proceduresin J. Heterocyclic Chem. 1992, 19, 1355.

Scheme 2 outlines the route to prepare carbamate-type derivatives, suchas Examples 1-2, and 70-72. An alternate method to preparingN,N-di-substituted carbamates utilized a nitrophenyl carbonateintermediate which may be treated with various primary or secondaryamines. Similarly urea, O-carbamate, and N-carbamate derivatives may beprepared from reaction of the appropriate amine or phenol intermediatewith an isocyanate or chloroformate or from the appropriate nitrophenylcarbonate, nitrophenyl carbamate, or trichloromethylcarbonyl (see J.Org. Chem. 2003, 68, 3733-3735).

Scheme 3 outlines a route to prepare heteroaryl ethers from thecorresponding phenol using a base such as sodium hydride and aheteroaryl bromide or chloride.

Scheme 4 shows a route for the preparation of N-carbamates (examples50-69) or amides (examples 74-82) from the corresponding anilineintermediates I-29. Amino intermediates I-29 were prepared by alkylationof the appropriate cyano-esters with the appropriate alkyl iodide orbromide followed by nitration, and subsequent RaNi reduction to providethe amino-lactam. The desired compounds were readily prepared from theamine.

Heteroaryl ketones may be prepared using standard Friedel-Crafts typeacylation reactions.

EXAMPLES

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments as shown in thefollowing Tables 1-5. The compounds of Tables 1-5 show activity in thetargets described herein at concentrations ranging from 0.1 nM to 10 μM.These examples are given for illustration of the invention and are notintended to be limiting thereof.

TABLE 1

Ex. No. R³ R² Q R⁵ 1

H CH₂CH₂ OiPr 2

H CH₂CH₂ OiPr 3

H CH₂CH₂ OiPr 4

H CH₂CH₂ OiPr 5

H CH₂CH₂ OiPr 6

CH₂CH₂CH₃ CH₂CH₂ O^(i)Pr 7

H CH₂CH₂ O^(i)Pr 8

CH₂CH₂CH₃ CH₂CH₂ O^(i)Pr 9 H CH₂CH₂OH CH₂CH₂

10 H

CH₂CH₂

11 H CH₂CH₂OH CH₂CH₂

12 H H CH₂CH₂

TABLE 2

*R¹ is H, unless otherwise noted Ex. No. R³ R² Q 13

H CH₂CH₂ 14

CH₂CH₃ CH₂CH₂ 15

CH₃ CH₂CH₂ 16

CH₂CH₂ 17

H CH₂CH₂ 18

CH₂CH₂CH₂CH₃ CH₂CH₂ 19

CH(CH₃)2 CH₂CH₂ 20

CH₂CH₂ 21

R² =

*R¹ =

CH₂CH₂ 22

CH₂CH(CH₃)₂ CH₂CH₂ 23

CH₂CH₃ CH₂CH₂ 24

CH₂CH(CH₃)₂ CH₂CH₂ 25

CH₂CH₃ CH₂CH₂ 26

H CH₂CH₂ 27

CH₂CH₃ CH₂CH₂ 28

H CH₂CH₂ 29

CH₂CH₂CH₃ CH₂CH₂ 30

CH₂CH(CH₃)₂ CH₂CH₂ 31

CH₂CH(CH₃)₂ CH₂CH₂ 32

CH₂CH═CH₂ CH₂CH₂ 33

CH₂COOEt CH₂CH₂ 34

CH₂COOH CH₂CH₂ 35

CH₂CH(CH₃)₂ CH₂CH₂ 36

CH₂CH(CH₃)₂ CH₂CH₂ 37

CH₂CH(CH₃)₂ CH₂CH₂ 38

CH₂CH(CH₃)₂ CH₂CH₂ 39

CH₂CH₂CH₃ CH₂CH₂ 40

CH(CH₃)₂ CH₂CH₂ 41

CH₂CH(CH₃)₂ CH₂CH₂ 42

CH₂CH₂NMe₂ CH₂CH₂ 43

CH₂CH₂ 44

CH₂CH₂ 45

CH₂CH(CH₃)₂ CH₂CH₂ 46

CH₂CH₂ 47

CH₂CH₂ 48

CH₂CH₂ 49

CH₂CH₂ 50

CH₂CH₂CH₃ CH₂CH₂ 51

CH₂CH₂CH₃ CH₂CH₂ 52

CH₂CH₂CH₃ CH₂CH₂ 53

CH₂CH₂CH₃ CH₂CH₂ 54

CH₂CH₂CH₃ CH₂CH₂ 55

CH₂CH₂CH₃ CH₂CH₂ 56

CH(CH₃)₂ CH₂CH₂ 57

CH₂CH(CH₃)₂ CH₂CH₂ 58

CH₂CH(CH₃)₂ CH₂CH₂ 59

CH₂CH(CH₃)₂ CH₂CH₂ 60

CH₂CH(CH₃)₂ CH₂CH₂ 61

CH(CH₃)₂ CH₂CH₂ 62

CH₂CH₂CH₃ CH₂CH₂ 63

CH₂CH(CH₃)₂ CH₂CH₂ 64

CH₂CH(CH₃)₂ CH₂CH₂ 65

CH₂CH(CH₃)₂ CH₂CH₂ 66

CH(CH₃)₂ CH₂CH₂ 67

CH(CH₃)₂ CH₂CH₂ 68

CH(CH₃)₂ CH₂CH₂ 69

CH(CH₃)₂ CH₂CH₂ 70

CH₂CH₃ CH₂CH₂ 71

CH₂CH(CH₃)₂ CH₂CH₂ 72

CH(CH₃)₂ CH₂CH₂ 73

CH₂CH(CH₃)₂ CH₂CH₂ 74

CH(CH₃)₂ CH₂CH₂ 75

CH₂CH₂CH₃ CH₂CH₂ 76

CH₂CH₂CH₃ CH₂CH₂ 77

CH(CH₃)₂ CH₂CH₂ 78

CH(CH₃)₂ CH₂CH₂ 79

CH₂CH(CH₃)₂ CH₂CH₂ 80

CH₂CH(CH₃)₂ CH₂CH₂ 81

CH₂CH₂CH₃ CH₂CH₂ 82

CH₂CH(CH₃)₂ CH₂CH₂

TABLE 3

Ex. No. R³ R² Q 83

CH₂CH(CH₃)₂ CH₂CH₂ 84

CH₂CH(CH₃)₂ CH₂CH₂ 85

CH₂CH(CH₃)₂ CH₂CH₂

TABLE 4 Example MS m/e No. Structure (M + 1) 86

509 87

511 88

493 89

454 90

464 91

482 92

457 93

486 94

502 95

514 96

562 97

528 98

555 99

487 100

459 101

500 102

472 103

488 104

459 105

548 106

585 107

430 108

569 109

541 110

557 111

529 112

563 113

577 114

535 115

549 116

571 117

598 118

543 119

570 120

507 121

525 122

521 123

535 124

549 125

576 126

549 127

537 128

542 129

573 130

563 131

589 132

577 133

565 134

604 135

577 200

543 201

575 202

590 203

576 204

577 205

607 206

621 207

593 208

564 209

607 210

629 211

579 212

593

TABLE 5

Eg. R³ R² Q R⁵ 136

CH₂CH₂CH₂OH CH₂ H 137

CH₂CH₂CH₂OH CH₂ H 138

CH₂CH₂CH₂OH CH₂ H 139

CH₂CH₂CH₂OH CH₂ H 140

CH₂CH₂CH₂OH CH₂ H 141

CH₂CH₂CH₂OH CH₂ H 142

CH₂CH₂CH₂OH CH₂ H 143

CH₂CH₂CH₂OH CH₂ H 144

CH₂CH₂CH₂OH CH₂ H 145

CH₂CH₂CH₂OH CH₂ H 146

CH₂CH₂CH₂OH CH₂ H 147

H CH₂CH₂ OCH₃ 148

CH₂CH₂OH CH₂ OCH₃ 149

CH₂CH₂OH CH₂CH₂ OCH₃ 150

CH₂CH₂CH₂OH CH₂ H 151

CH₂CH₂CH₂OH CH₂ H 152

H CH₂ H 153

H CH₂ H 154

H CH₂ H 155

H CH₂ H 156

H CH₂ OCH₃ 157

CH₂ H 158

CH₂CH(OH)—CH₃ CH₂ H 159

H CH(OH)CH₃ H 160

CH₂CH₂OH CH₂CH₂ OCH₃ 161

H CH₂CH₂ OiPr 162

CH₂CH₂OH CH₂CH₂ OCH₃ 163

H CH₂CH₂ OCH₃ 164

H CH₂CH₂ OiPr 165

H CH₂CH₂ OiPr 166

H CH₂CH₂ OiPr 167 H CH₂CH₂OH CH₂CH₂

168 H CH₂CH₂OH CH₂CH₂ O(CH₂)₂OH 169 H CH₂CH₂OH CH₂CH₂

170 H CH₂CH₂OH CH₂CH₂ O[(CH₂)₂O]₂Me 171 H CH₂CH₂OH CH₂CH₂

172 H CH₂CH₂OH CH₂CH₂

173 H CH₂CH₂OH CH₂CH₂

174 H CH₂CH₂OH CH₂CH₂

175 H CH₂CH₂OH CH₂CH₂ OCH(CH₃)CO₂Et 176 H CH₂CH₂OH CH₂CH₂

177 H CH₂CH₂OH CH₂CH₂ OCH₂CO₂tBu 178 H H CH₂CH₂

179 H CH₂CH₂OH CH₂CH₂ OCH₂CO₂Et 180 H CH₂CH₂OH CH₂CH₂

181 H CH₂CH₂OH CH₂CH₂ O(CH₂)₂OMe 182 H CH₂CH₂OH CH₂CH₂ O(CH₂)₃CN 183 HCH₂CH₂OH CH₂CH₂ O(CH₂)₅CN 184 H CH₂CH₂OH CH₂CH₂ O(CH₂)₂OEt 185 HCH₂CH₂OH CH₂CH₂ O(CH₂)₄CN 186 H CH₂CH₂OH CH₂CH₂ O(CH₂)₆CN 187 H CH₂CH₂OHCH₂CH₂ OCH₂CN 188 H CH₂CH₂OH CH₂CH₂ O(CH₂)₄C(═NH)OEt 189 H CH₂CH₂OHCH₂CH₂ O(CH₂)₄CO₂H 190 H CH₂CH₂OH CH₂CH₂ O(CH₂)₆CONH₂ 191 H CH₂CO₂Et CH₂OCH₂CO₂Et 192 H H CH₂ OCH₂CO₂Et 193 H H CH₂ OCH₂CN 194 H H CH₂ OCH₂CH₂OH195 H CH₂CH₂OH CH₂ OCH₂CH₂OH 196 H H CH₂ OCH₂CH(OH)CH₂OH 197 H H CH₂OCH₂CONMe₂ 198 H H CH₂ OCH₂CH(OH)CH₂NMe₂ 199 H H CH₂

General Procedure for Examples 1 and 2.

A mixture of phenol intermediate I-14 (0.05 mmol.), isocyanate (0.05mmol.), cesium hydrogen carbonate (0.5 mg) and tetrahydrofuran (0.5 mL)was stirred at room temperature for 1 day. The solvent was evaporatedand the residue stirred for 8 hours with ethyl acetate and 3N HCl. Theethyl acetate was removed by evaporation and the aqueous solution wasdecanted from the solid. The residue was triturated with methanol andthe product collected.

Example 1

(26%) MS m/e 510 (M+1); ¹H NMR (DMSO-d₆) δ 11.60 (s, 1H), 8.33 (s, 1H),8.16 (d, 1H), 7.63 (d, 1H), 7.53 (s, 1H), 7.51 (d, 1H), 7.18 (d, 1H),6.86 (s, 1H), 6.77 (d, 1H), 4.77 (s, 2H), 4.68 (m, 1H), 3.87 (m, 1H),2.98 (t, 2H), 2.83 (t, 2H), 1.85 (m, 2H), 1.69 (m, 2H), 1.52 (m, 4H),1.31 (d, 6H).

Example 2

(36%) MS m/e 524 (M+1); ¹H NMR (DMSO-d₆) 11.59 (s, 1H), 8.33 (s, 1H),8.16 (d, 1H), 7.63 (s, 1H), 7.52 (d, 1H), 7.17 (d, 1H), 6.86 (s, 1H),6.78 (d, 1H), 4.77 9s, 2H), 4.68 m, 1H), 3.00 (t, 2H), 2.83 (t, 2H),1.87 (m, 2H), 1.72 (m, 2H), 1.56 (d, 1H), 1.30 (d, 6H).

Example 3

A suspension of sodium hydride (2.44 mg, 1.22 eq.) in 0.5 mL of THF wasstirred under N₂ as phenol intermediate I-14 (20.6 mg, 0.05 mmol) in 2.0mL of THF:DMF (1:1) was added dropwise. After 10 minutes of stirring,2-bromopyrimidine (8.9 mg, 1.12 equivalents) in 0.5 mL of THF was added.The mixture was stirred at 60° C. for 14 hours. The mixture was cooledto room temperature, diluted with CH₂Cl₂/MeOH, filtered through celiteand concentrated. Purification was achieved by preparative TLC withCH₂Cl₂/MeOH (9:1) to afford the product (4.0 mg, 17%) (MS: 477 m/e(M+H)⁺).

Example 4

The compound was prepared according to the procedure of Example 3 usingphenol intermediate I-14 and 2-chlorobenzoxazole; 40 hr; preparative TLC(10% MeOH in CH₂Cl₂); yield 28%; MS: 516 m/e (M+1)⁺.

Example 5

The compound was prepared according to the procedure of Example 3 usingintermediate I-14 and 2-chlorobenzothiazole; 40 hr; preparative TLC (10%MeOH in CH₂Cl₂); yield 13%; MS: 531 m/e (M+1)⁺.

Example 6

To a mixture of Example 3 (25.0 mg, 0.052 mmol) and cesium carbonate (81mg, 5.0 eq) in 2.0 mL of CH₃CN was added n-propyl bromide (47 ul, 10.0eq.) under N₂. After stirring at 90° C. for 14 hours, the mixture wasdiluted with CH₂Cl₂, filtered through celite and concentrated.Purification by preparative TLC with 95% of CH₂Cl₂/MeOH afforded theproduct (15.0 mg, 56%); MS: m/e 519 (M+1)⁺.

Example 7

The compound was prepared using to the procedure of Example 3 usingintermediate I-14 and 2-bromopyrazine; preparative TLC (10% MeOH inCH₂Cl₂); MS 499 m/e (M+1)⁺.

Example 8

The compound was prepared according to the procedure of Example 6 usingExample 7 as starting material. MS m/e 519 (M+1).

Synthesis of Phenol Intermediates I-18 and I-19.

A mixture of AlCl₃ (800 mg, 6 mmol) in dichloroethane (8 mL) was stirredat 0° C. as EtSH (1.40 mL) was added and followed by intermediate I-41(398 mg, 1 mmol). The reaction was stirred at 50° C. for 48 hr. To thereaction mixture was added 5 mL of 1N HCl and the mixture was stirred atrt for 0.5 hr. Filtration provided 240 mg (63%) of intermediate I-18(MS: 385 m/e (M+1)⁺. By a similar method intermediate I-19 was preparedfrom the methoxy N—H derivative.

Examples 9 and 10

A suspension of sodium hydride (12.2 mg, 1.22 eq.) in 0.5 mL of THF wasstirred under N₂ as phenol intermediate I-18 (76.8 mg, 0.2 mmol) in 4.0mL of THF:DMF (1:1) was added dropwise at room temperature. After 10minutes stirring, 2-chloro-benzothiazole (38 mg, 1.12 eq.) in 0.5 mL ofTHF was added. The mixture was then stirred at 60° C. for 40 hours,diluted with CH₂Cl₂/MeOH, filtered through celite and concentrated.Purification by preparative TLC with (9:1) CH₂Cl₂/MeOH afforded the monoproduct Example 9 (6.0 mg, yield 6%) (MS: 517 m/e (M+H)⁺) and thedialkylated product Example 10 (60 mg, yield 46%) (MS: 651 m/e (M+H)⁺).

Example 11

The compound was prepared according to the procedure of Example 10 usingphenol intermediate I-18 and 2-chlorobenzoxazole; 36 hr; preparative TLC(10% MeOH in CH₂Cl₂); yield 11%; MS: 502 m/e (M+1)⁺.

Example 12

The compound was prepared according to the procedure of Example 10 usingintermediate I-19 and 2-bromopyrimidine; 36 hr; preparative TLC (10%MeOH in CH₂Cl₂); yield 25%; MS: 419 m/e (M+1)⁺.

Example 13

The compound was prepared according to the procedure for Example 3 usingphenol intermediate I-22 and 2-bromopyrimidine; 30 hr; preparative TLC(10% MeOH in CH₂Cl₂); yield 53%; MS: 423 m/e (M+1)⁺.

Example 14

The compound was prepared according to the procedure for Example 6 usingExample 13 and iodoethane; 14 hr; preparative TLC (10% MeOH in CH₂Cl₂);yield 19%; MS: 451 m/e (M+1)⁺.

Example 15

The compound was prepared according to the procedure for Example 6 usingExample 13 and iodomethane; 14 hr; preparative TLC (10% MeOH in CH₂Cl₂);yield 28%; MS: 459 m/e (M+23)⁺.

Example 16

The compound was prepared according to the procedure for Example 6 usingExample 13 and cyclopentyl bromide; 14 hr; preparative TLC (10% MeOH inCH₂Cl₂); yield 38%; MS: 513 m/e (M+23)⁺.

Example 17

A mixture of phenol intermediate I-22 (17.2 mg, 0.05 mmol), potassiumt-butoxide (33.7 mg, 6 eq.) and t-butylammonium bromide (0.97 mg, 0.06eq) was mixed and stirred for 5 minutes, then 1.0 mL of chloropyrazinewas added, then stirred at room temperature for 5 minutes and at 90° C.for 1 hour. The mixture was cooled to room temperature, excess of thechloropyrazine was evaporated off and the resulting residue was dilutedwith CH₂Cl₂ MeOH. Purification by preparative TLC with (9:1) CH₂Cl₂/MeOHafforded the mono product (11.0 mg, yield 52%) MS: 423 m/e (M+1)⁺.

Example 18

The compound was prepared according to the procedure for Example 6 usingExample 13 and butyl bromide; 14 hr; preparative TLC (10% MeOH inCH₂Cl₂); yield 38%; MS: 479 m/e (M+1)⁺.

Example 19

The compound was prepared according to the procedure for Example 10using Example 13 and 2-propyl bromide; 60 hr; preparative TLC (10% MeOHin CH₂Cl₂); yield 10%; MS: 465 m/e (M+1)⁺.

Example 20

The compound was prepared according to the procedure for Example 6 usingExample 13 and 2-cyclopropylmethyl bromide; 14 hr; preparative TLC (10%MeOH in CH₂Cl₂); yield 5%; MS: 477 m/e (M+1)⁺.

Example 21

The compound was prepared according to the procedure for Example 6 usingExample 13 and 2-cyclopropylmethyl bromide; 14 hr; preparative TLC (10%MeOH in CH₂Cl₂); MS: 507 m/e (M+1)⁺.

Example 22

The compound was prepared according to the procedure for Example 6 usingExample 13 and isobutyl bromide; preparative TLC (10% MeOH in CH₂Cl₂);MS: 493 m/e (M+1)⁺.

Example 23

The compound was prepared according to the procedure for Example 6 usingExample 17 and ethyl iodide; preparative TLC (10% MeOH in CH₂Cl₂); MS:451 m/e (M+1)⁺.

Example 24

The compound was prepared according to the procedure for Example 6 usingExample 13 and 1-bromo-3,5-dimethoxytriazine; preparative TLC (10% MeOHin CH₂Cl₂); MS: 540 m/e (M+1)⁺.

Example 25

To 25 mg (0.07 mmol) of the N-ethyl intermediate I-23-1 in methylenechloride/nitromethane (3 mL/2 mL) was slowly added 2-furoyl chloride (69μl, 0.7 mmol, 10 eq) followed by aluminum chloride (93 mg, 0.7 mmol, 10eq). The reaction was stirred at room temperature overnight. Thereaction mixture was concentrated, water and a few drops of 1N HCl wereadded to the residue and the mixture was extracted with methylenechloride. The combined organic extracts were dried with sodium sulfate,the drying agents removed by filtration, and the solvent was removed byevaporation. The crude mixture was dissolved in methanol/methylenechloride and purified by preparative TLC eluting with 10%methanol/methylene chloride. The desired band was collected, stirredwith methylene chloride/methanol, filtered through a fritted funnel, andconcentrated. The sample was dried at 80° C. under high vacuumovernight. MS m/e 451 (M+1).

Example 26

The compound was prepared by the method described for Example 25. MS m/e438 (M+1).

Example 27

To the N-ethyl intermediate I-23-1 (25 mg, 0.07 mmol) in nitromethane (5mL) was added 2-thiophene carbonyl chloride (75 μl 0.7 mmol, 10 eq)followed by addition of aluminum chloride (94 mg, 0.7 mmol, 10 eq) insmall portions. The reaction mixture was stirred at room temperatureovernight. The reaction was then concentrated, stirred with water and afew drops of 1 N HCl were added. The product was collected byfiltration, dissolved in methylene chloride/methanol and purified bypreparative TLC eluting with 10% methanol/methylene chloride. Thedesired band was collected, stirred with methylene chloride/methanol,filtered, and concentrated. The sample was dried at 80° C. under vacuumovernight. MS m/e 467 (M+1).

Examples 28-49 were prepared using the general method described forExample 27 using the appropriate N-alkyl intermediate I-23, andheteroaryl acid chloride with AlCl₃ or FeCl₃ as catalyst.

Example 28

MS m/e 423 (M+1)

Example 29

MS m/e 465 (M+1)

Example 30

MS m/e 479 (M+1)

Example 31

MS m/e 495 (M+1)

Example 32

MS m/e 463 (M+1)

Example 33

MS m/e 509 (M+1)

Example 34

MS m/e 481 (M+1)

Example 35

MS m/e 530 (M+1)

Example 36

MS m/e 495 (M+1)

Example 37

MS m/e 479 (M+1)

Example 38

MS m/e 574 (M+1)

Example 39

MS m/e 481 (M+1)

Example 40

MS m/e 481 (M+1)

Example 41

MS m/e 608 (M+1)

Example 42

MS m/e 588 (M+1)

Example 43

MS m/e 536 (M+1)

Example 44

MS m/e 520 (M+1)

Example 45

MS m/e 509 (M+1)

Example 46

MS m/e 592 (M+1)

Example 47

MS m/e 550 (M+1)

Example 48

MS m/e 550 (M+1)

Example 49

MS m/e 570 (M+1)

Example 50

To a stirred solution of 3-amino intermediate I-29-2 (25 mg, 0.0649mmol) in CH₂Cl₂ (5 mL) was added isopropyl chloroformate (1.0 M intoluene, 125 μL, 0.125 mmol) and pyridine (20 μL, 0.247 mmol). Afterstirring 3 h at room temperature, the resulting precipitate was filteredand dried to give 28 mg (91%) of the desired product. ¹H NMR (DMSO-d₆) δ9.51 (s, 1H), 8.85 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.61-7.49 (m,2H), 4.98 (m, 1H), 4.68 (s, 2H), 4.51 (m, 2H), 3.86 (s, 3H),3.45 (m,2H), 2.83 (m, 2H), 1.80 (m, 2H), 1.29 (m, 6H), 0.89 (m, 3H); MS (m/e)472 (M+1).

Example 51

MS m/e 458 (M+H).

Example 52

MS m/e 486 (M+H).

Example 53

MS m/e 472 (M+H).

Example 54

MS m/e 476 (M+H).

Example 55

MS m/e 492 (M+H).

Example 56

MS m/e 458 (M+H).

Example 57

MS m/e 500 (M+H).

Example 58

MS m/e 486 (M+H).

Example 59

MS m/e 486 (M+H).

Example 60

MS m/e 472 (M+H).

Example 61

MS m/e 472 (M+H).

Example 62

MS m/e 536 (M+H).

Example 63

MS m/e 490 (M+H).

Example 64

MS m/e 506 (M+H).

Example 65

MS m/e 550 (M+H).

Example 66

MS m/e 486 (M+H).

Example 68

To 25 mg (0.045 mmol) of the N-p-nitrophenyl intermediate was added 500μl N-piperidinylethanol. The reaction was stirred at room temperaturefor approximately 5 hours, diluted with methylene chloride, washed withwater/brine and dried over sodium sulfate. The crude product waspurified by preparative TLC eluting with 8-10% MeOH/CH₂Cl₂. The pureproduct was collected, stirred with solvent, filtered, and concentrated.The sample was dried at 80° C. under high vacuum. ¹H NMR (DMSO-d₆) δ9.80 (s, 1H), 8.77 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 7.72 (d, 1H),7.50 (d, 1H), 5.20 (m, 1H), 4.78 (s, 2H), 4.19 (m, 2H), 3.86 (s, 3H),2.78 (m, 2H), 2.41 (m, 4H), 1.59 (d, 6H), 1.40 (m, 10H). MS m/e 541(M+1).

Example 67

The compound was prepared by the method described for Example 68 usingthe N-p-nitrophenyl intermediate and N-pyrrolidinylethanol. MS m/e 527(M+1).

Example 69

The compound was prepared by the method described for Example 68 usingthe N-p-nitrophenyl intermediate and N-pyrrolidinylethanol. MS m/e 538(M+1).

Example 70

Step 1: O-Nitrophenylcarbonate intermediate: A mixture of the phenolintermediate I-33-1 (192 mg, 0.525 mmol) and p-nitrophenyl carbonate(314 mg, 1.03 mmol) in DMF (4 mL) was heated to 100° C. for 20 h.Solvent was removed by rotary evaporation and the residue was extractedinto CH₂Cl₂ and washed with aqueous NaHCO₃. The organic layer was driedover MgSO₄, filtered, and evaporated. The resulting residue was purifiedby column chromatography (silica gel, 3% MeOH in CH₂Cl₂) to afford thecarbonate intermediate (156 mg, 56%). ¹H NMR (CDCl₃) δ 8.86 (s, 1H),8.34 (d, 2H, J=9.1), 7.69 (d, 1H, J=2.1), 7.53 (d, 2H, J=9.1), 7.49, (d,1H, J=8.8), 7.41, (d, 1H, J=8.8), 6.01 (s, 1H), 4.84 (s, 2H), 4.62 (q,2H, J=7.1), 3.96 (s, 3H), 3.55 (t, 2H, 8.0), 3.01 (t, 2H, J=8.0), 1.55(t, 3H, J=7.1). MS m/e 538 (M+H).

Step 2: A suspension of the carbonate intermediate (52 mg, 97 umol) inTHF (2 mL) was treated with pyrrolidine (20 uL, 227 umol). The mixturewas warmed to 40° C. for 2 h. Solvent was removed by rotary evaporation,and the residue was extracted into CH₂Cl₂ and washed with dilute aqueousNaOH. The organic layer was dried over MgSO₄, filtered, and evaporated.The resulting residue was purified by triturating with water (2×1 mL)and ether (2×1 mL). ¹H NMR (CDCl₃, δ) 8.86 (s, 1H), 7.55 (d, 1H, J=2.1),7.40, (d, 1H, J=8.8), 7.26, (d, 1H, J=8.8), 6.01 (s, 1H), 4.78 (s, 2H),4.57 (q, 2H, J=7.1), 3.95 (s, 3H), 3.65 (t, 2H, 7.0), 3.55-3.45 (m, 4H),2.99 (t, 2H, J=7.0), 2.02-1.96 (m, 4H), 1.53 (t, 3H, J=7.1). MS m/e 470(M+H).

Example 71

MS m/e 498 (M+H).

Example 72

MS m/e 484 (M+H).

Example 73

MS m/e 555 (M+H).

Example 74

To 20 mg (0.052 mmol) of the amine intermediate I-29-1 in 2 mLCH₂Cl₂/12.6 μl pyridine was added 28 mg (0.156 mmol, 3 eq.) nicotinoylchloride. The reaction was heated to 49° C. for 1 hr, cooled to roomtemperature, concentrated, stirred with ether, and the solid wasfiltered off. The solid was taken up in CH₂Cl₂/MeOH and purified onpreparative TLC eluting with 10% MeOH/CH₂Cl₂. The pure product wascollected and dried at 80° C. under high vacuum. ¹H NMR (DMSO-d₆) 10.53(s, 1H), 9.18 (s, 1H), 8.79 (s, 2H), 8.40 (m, 3H), 7.83 (s, 2H), 7.6 (m,1H), 5.25 (m, 1H), 4.74 (s, 2H), 3.87 (s, 3H), 3.41 (m, 2H), 2.80 (m,2H), 1.61 (d, 6H). MS m/e 491(M+1).

Examples 75-82 were prepared by the method described for Example 74using the appropriate amine intermediate I-29 and acid chloride.

Example 75

MS m/e 496 (M+H).

Example 76

MS m/e 480 (M+H).

Example 77

MS m/e 491 (M+H).

Example 78

MS m/e 491 (M+H).

Example 79

MS m/e 510 (M+H).

Example 80

MS m/e 494 (M+H).

Example 81

MS m/e 481 (M+H).

Example 82

MS m/e 495 (M+H).

Example 83

The compound was prepared using the N-sec-butyl intermediate I-36 and2-thiophene carbonyl chloride by the general procedure described forExample 25. MS m/e 495 (M+H).

Example 84

The compound was prepared using the N-sec-butyl indazole intermediateI-36 and 2-furoyl chloride by the general procedure described forExample 25. MS m/e 479 (M+H).

Example 85

The compound was prepared using the intermediate I-39 by the generalprocedure described for Example 13. MS m/e 479 (M+H).

General Procedure A for Examples 136-140.

A solution of diol intermediate I in the appropriate alcohol (0.05 M) ina sealable glass reaction tube was added camphorsulfonic acid (1.1equiv.). The reaction tube was flushed with nitrogen and sealed. Thereaction mixture was heated to 80° C. for 2-26 h and monitored for lossof starting material by HPLC. Upon completion of the reaction themixture was cooled to room temperature and poured into ether. Theprecipitate that formed was collected by filtration and purified byflash chromatography or preparative TLC on silica gel using ethylacetate or a mixture ethyl acetate and hexane to yield the pureproducts. The following Examples were prepared.

Example 136

Tan solid (58% yield). ¹H NMR (CDCl₃, 300 MHz): δ 2.03 (m, 2H), 2.13 (m,2H), 2.40 (m, 2H), 3.56 (m, 4H), 3.72 (m, 4H), 4.37 (s, 2H), 4.71 (s,4H), 4.89 (s, 2H), 6.12 (s, 1H), 7.34-7.62 (6H, m), 7.99 (s, 1H), 9.53(d, 1H); MS (ESI): m/e 510 (M+1)⁺;

Example 137

(71% yield). ¹H NMR (CDCl₃, 300 MHz): δ 1.97 (t, 2H), 3.61 (t, 2H), 3.79(m, 4H), 4.14 (s, 2H), 4.41 (m, 4H), 4.62 (s, 2H), 4.76 (s, 2H), 6.10(s, 1H), 7.28-7.57 (m, 11H), 7.68 (s, 1H), 9.47 (d, 1H); MS (ESI): m/e533 (M+1)⁺; 555 (M+Na)⁺.

Example 138

(19% yield). ¹H NMR (CDCl₃, 300 MHz): δ 1.66 (m, 1H), 2.01-2.22 (m, 3H),2.67 (m, 1H), 3.51 (m, 2H), 3.74 (m, 4H), 3.88 (m, 2H), 4.38 (s, 2H),4.71 (s, 2H), 4.72 (m, 2H), 4.90 (s, 2H), 6.07 (s, 1H), 7.36 (t, 1H),7.44-7.68 (m, 5H), 7.80 (s, 1H), 9.53 (d, 1H); MS (ESI): m/e 483 (M+1)⁺;

Example 139

(21.2 mg) ¹H NMR (CDCl₃, 300 MHz): δ 1.95 (m, 2H), 2.04 (s, 3H), 2.68(t, 2H), 3.49 (m, 2H), 3.64 (t, 2H), 4.52 (s, 2H), 4.66 (s, 2H), 4.73(m, 2H), 4.90 (s, 2H), 7.27-7.43 (m, 2H), 7.48 (d, 1H), 7.63 (d, 1H),7.69 (d, 1H), 7.94 (s, 1H), 8.55 (s, 1H), 9.46 (d, 1H); MS (ESI): m/e473 (M+1)⁺;

Example 140

off-white solid (25% yield). ¹H NMR (CDCl₃, 300 MHz): δ 1.93 (m, 2H),3.22 (s, 3H), 3.46 (m, 4H), 3.58 (m, 2H), 4.49 (s, 2H), 4.64 (s, 2H),4.70 (m, 2H), 4.78 (m, 1H), 4.87 (s, 2H), 7.23-7.43 (m, 2H), 7.47 (d,1H), 7.62 (d, 1H), 7.70 (d, 1H), 7.89 (s, 1H), 8.54 (s, 1H), 9.46 (d,1H);

General Procedure B Examples 141-144.

In a sealed reaction tube, a suspension of the diol intermediate I (1equivalent) in either the appropriate alcohol or methylene chloride orchloroform containing the appropriate alcohol, at room temperature wasadded trifluoroacetic anhydride (1-2 equiv.) slowly. The tube wasflushed with nitrogen and sealed tightly. The mixture was stirred atroom temperature for 1-2 hours then heated to 80° C. for 2-60 h andmonitored for disappearance of starting material by HPLC. Uponcompletion the reaction was allowed to cool to room temperature,concentrated and worked up by both triturating the residue with etherand collecting the resulting precipitate by filtration, or extraction ofthe product from the reaction mixture with a suitable organic solvent.The solid product was purified by triturating with ether or flashchromatography on silica gel using ethyl acetate or a mixture of ethylacetate and hexane. The following Examples were prepared.

Example 141

Light yellow solid (17% yield). ¹H NMR (DMSO-d6, 300 MHz): δ 1.93 (m,2H), 3.45 (m, 6H), 3.58 (s, 4H), 4.53 (s, 2H), 4.56 (m, 1H), 4.65 (s,2H), 4.74 (m, 3H), 4.91 (s, 2H), 7.33-7.39 (m, 2H), 7.48 (d, 1H),7.63-7.71 (m, 2H), 7.92 (s, 1H), 8.55 (s, 1H), 9.47 (d, 1H); MS (ESI):m/e 487 (M+1)⁺, 509 (M+Na)⁺.

Example 142

Pale yellow solid (26% yield). ¹H NMR (CDCl₃, 300 MHz): δ 1.33 (d, 3H),2.11 (m, 2H), 3.19 (m, 1H), 3.56-3.77 (m, 4H), 4.30 (s, 2H), 4.65 (m,2H), 4.68 (s, 2H), 4.74 (s, 2H), 6.07 (s, 1H), 7.20-7.50 (m, 1H), 7.56(d, 1H), 7.69 (s, 1H), 9.48 (d, 1H); MS (ESI): m/e 517 (M+1)⁺, 539(M+Na)⁺.

Example 143

Orange residue (21% yield). ¹H NMR (DMSO-d6, 300 MHz): δ 1.93 (m, 2H),2.30 (m, 4H), 2.50 (m, 2H), 3.48 (m, 6H), 3.94 (s, 2H), 4.52 (s, 2H),4.72 (m, 4H), 4.88 (s, 2H), 7.33-7.43 (m, 2H), 7.48 (d, 1H), 7.66 (m,2H), 7.88 (s, 1H), 8.57 (s, 1H), 9.46 (d, 1H); MS (ESI): m/e 528 (M+1)⁺.

Example 144

Light orange solid (9% yield). ¹H NMR (DMSO-d6, 300 MHz): δ 1.29 (m,2H), 1.39 (m, 4H), 1.95 (m, 2H), 2.26 (m, 4H), 2.51 (m, 2H), 3.47 (m,2H), 3.94 (s, 2H), 4.52 (s, 2H), 4.72 (m, 4H), 4.88 (s, 2H), 7.33-7.39(m, 2H), 7.47 (d, 1H), 7.66 (m, 2H), 7.88 (s, 1H), 8.57 (s, 1H), 9.46(d, 1H); MS (ESI): m/e 526 (M+1)⁺.

General procedure C for Examples 145-156:

To a well-stirred suspension of the CH₂OH intermediates I, II, or III in7 mL of methylene chloride were added sequentially trifluoroaceticanhydride (5 equivalents) and N-methyl morpholine (5 eq) at 5° C. andunder argon atmosphere. The resulted suspension was stirred at roomtemperature for 3 hours and the low boiling solvents were removed undervacuum. A stirred solution of this tritrifluoroacetate intermediate inan appropriate alcohol was heated to 80° C. for 6-48 hours in an oilbath. Gradually, the heterogeneous reaction mixture became homogeneous.When no starting material was observed by HPLC the reaction mixture wasworked up by removing the solvent in vacuo. The residues was purified byeither triturating with water or ether or alternatively, flashchromatography or preparative plate chromatography on silica gel usingethyl acetate or an ethyl acetate/hexane mixture.

Example 145

(12.6 mg, 44% yield). ¹H NMR (CDCl₃, 300 MHz): δ 2.18 (m, 2H), 2.09 (m,1H), 3.73 (m, 4H), 4.42 (s, 2H), 4.76 (s, 2H), 4.80 (m, 2H), 4.98 (s,2H), 6.12 (s, 1H), 7.23 (m, 2H), 7.43 (m, 2H), 7.48 (m, 2H), 7.68 (m,1H), 7.88 (s, 1H), 9.56 (d, 1H); MS (ESI): m/e 451 (M+1)⁺, 473 (M+Na)⁺.

Example 146

Light orange solid (35.3 mg, 74% yield). ¹H NMR (DMSO-d6, 300 MHz): δ1.23 (m, 2H), 1.50 (m, 4H), 1.67 (m, 2H), 1.93 (m, 2H), 2.13 (m, 1H),3.35 (m, 2H), 3.48 (m, 2H), 4.52 (s, 2H), 4.62 (s, 2H), 4.72 (m, 2H),4.89 (s, 2H), 7.33-7.39 (m, 2H), 7.47 (d, 1H), 7.62-7.70 (m, 2H), 7.90(d, 1H), 8.53 (s, 1H), 9.47 (d, 1H); MS (ESI): m/e 481 (M+1)⁺.

Example 147

Pale yellow solid (31 mg, 54% yield). ¹H NMR (DMSO-d6, 300 MHz): δ 0.05(m, 2H), 0.49 (m, 2H), 1.06 (m, 1H), 2.79 (m, 2H), 3.82 (m, 5H), 4.65(m, 4H), 4.79 (s, 2H), 4.97 (t, 1H), 6.80 (d, 1H), 6.89 (s, 1H), 7.46(d, 1H), 7.65 (d, 1H), 7.87 (s, 1H), 7.89 (d, 1H), 8.36 (s, 1H); MS(ESI): m/e 483 (M+1)⁺.

Example 148

Pale orange solid (12.4 mg, 24% yield). ¹H NMR (DMSO-d6, 300 MHz): δ2.79 (m, 2H), 3.12 (t, 2H), 3.30 (m, 2H), 3.72 (t, 2H), 3.82 (m, 5H),4.65 (m, 2H), 4.70 (s, 2H), 4.76 (s, 2H), 4.97 (t, 2H), 6.79 (d, 1H),6.90 (s, 1H), 6.93 (s, 1H), 6.97 (d, 2H), 7.35 (s, 1H), 7.46 (d, 1H),7.65 (d, 1H), 7.89 (d, 2H), 8.39 (s, 1H); MS (ESI): m/e 539 (M+1)⁺.

Example 149

Pale yellow solid (42.6 mg, 57% yield). ¹H NMR (DMSO-d6, 300 MHz): δ2.55 (m, 2H), 2.80 (t, 2H), 3.86 (m, 4H), 3.98 (s, 2H), 4.61 (s, 1H),4.73 (t, 1H), 4.80 (s, 2H), 4.98 (t, 1H), 6.78 (d, 1H), 6.89 (s, 1H),7.50 (d, 1H), 7.68 (d, 1H), 7.88 (s, 1H), 7.90 (d, 1H), 8.38 (s, 1H); MS(ESI): m/e 489 (M+1)⁺, 512 (M+Na)⁺.

Example 150

Yellow-tan solid (77% yield). ¹H NMR (DMSO-d6, 300 MHz): δ 0.2 (m, 2H),0.47 (m, 2H), 1.05 (m, 1H), 1.94 (m, 2H), 3.49 (m, 2H), 4.53 (s, 2H),4.64 (s, 2H), 4.75 (m, 2H), 4.92 (s, 2H), 7.32-7.45 (m, 2H), 7.49 (d,1H), 7.62-7.77 (m, 2H), 7.93 (s, 1H), 8.64 (s, 1H), 9.47 (d, 1H); MS(ESI): m/e 453 (M+1)⁺.

Example 151

Tan solid (32% yield). ¹H NMR (DMSO-d6, 300 MHz): δ 1.97 (m, 4H), 3.51(s, 2H), 3.73 (t, 2H), 4.56 (s, 2H), 4.71 (s, 2H), 4.77 (m, 2H), 4.91(s, 2H), 6.98 (m, 2H), 7.35-7.43 (m, 3H), 7.52 (d, 1H), 7.70 (m, 2H),7.96 (s, 1H), 8.60 (s, 1H), 9.51 (d, 1H); MS (ESI): m/e 509 (M+1)⁺.

Example 152

Yellow solid (69%). ¹H NMR (DMSO-d6, 300 MHz): δ 1.62-2.00 (m, 8H), 2.54(m, 1H), 3.38-3.50 (m, 4H), 4.51 (s, 2H), 4.61 (s, 2H), 4.72 (m, 2H),4.89 (s, 2H), 7.3-7.41 (m, 2H), 7.46 (d, 1H), 7.62-7.70 (m, 2H), 7.89(s, 1H), 8.53 (s, 1H), 9.47 (d, 1H); MS (ESI): m/e 467 (M+1)⁺.

Example 153

(80%) ¹H NMR (DMSO-d6, 300 MHz): δ 1.55 (m, 3H), 3.4-3.8 (m, 6H), 4.14(m, 2H), 4.66 (s, 2H), 4.91 (s, 2H), 7.29-7.73 (m, 5H), 7.98 (s, 1H),8.55 (s, 1H), 9.39 (d, 1H), 11.94 (s, 1H).

Example 154

(150 mg, 89% yield). ¹H NMR (DMSO-d6, 300 MHz): δ 1.80 (m, 4H),3.58-3.78 (m, 4H), 4.02 (m, 1H), 4.18 (s, 2H), 4.69 (s, 2H), 4.93 (s,2H), 7.34-7.49 (m, 2H), 7.56 (t, 2H), 7.70 (d, 1H), 7.94 (s, 1H), 8.53(s, 1H), 9.39 (d, 1H), 11.92 (s, 1H).

Example 155

¹H NMR (DMSO-d6, 300 MHz): δ 3.24 (s, 3H), 3.47 (m, 2H), 3.58 (m, 2H),4.13 (m, 2H), 4.62 (s, 2H), 4.89 (s, 2H), 7.30-7.42 (m, 3H), 7.56 (d,1H), 7.64 (d, 1H), 7.91 (s, 1H), 8.51 (s, 1H), 9.35 (d, 1H), 11.89 (s,1H); MS (ESI): m/e 421 (M+Na)⁺.

Example 156

(10%). MS m/e 429 (M+1); ¹H-NMR δ (DMSO-d₆) 11.79 (s, 1H), 9.20 (d, 1H),8.44 (s, 1H), 7.87 (s, 1H), 7.52 (d, 1H), 7.38 (d,1H), 7.24 (s, 1H),6.96 (d,1H), 4.86 (s,2H), 4.61 (s,2H), 4.08 (s,2H), 3.81 (s,4H), 3.58(d,1H), 3.52 (d,1H).

Example 157

A stirred solution of Example 155 (370 mg, 0.93 mmol) in DMF (20 mL) wasplaced under vacuum and DMF (10 mL) was removed by distillation. Themixture was cooled to room temperature and sodium hydride (45 mg, 0.93mmol) was added and stirred for 30 min. Glycidol mesylate (170 mg, 1.1mmol) was added and the reaction mixture heated to 60° C. After 18 h,the mixture was cooled to room temperature, filtered, and concentratedin vacuo. The solid was triturated with methanol, filtered, and purifiedby flash chromatography on silica gel using hexane/ethyl acetate (1:1)then methanol/ethyl acetate (10%) to give product (90 mg, 22% yield). MS(ESI): m/e 455 (M+1)⁺.

Example 158

To a stirred solution of Example 157 (80 mg, 0.18 mmol) in THF (10 mL)was added super hydride (724 uL, 0.72 mmol) dropwise at 0° C. Thereaction mixture was warmed to room temperature and stirred for 2 h. Thereaction solvent was removed in vacuo and 1N HCl was added. The mixturewas stirred, filtered, triturated with methanol and collected byfiltration. The solid was purified by flash chromatography usinghexane/ethyl acetate (3:1) to ethyl acetate (100%). Further purificationof the solid involved crystallization from ethyl acetate/methanolfollowed by acetonitrile to give product (40 mg, 50% yield). MS (ESI):m/e 457 (M+1)⁺.

Example 159

Using the general procedure for Example 158, a suspension of ester (1.45g, 2.27 mmol) in methylene chloride (30 mL) was cooled to 0° C. andDIBAL-H (5.7 mL, 5.7 mmol) was added dropwise. The reaction mixture waswarmed to room temperature for 2 h then quenched with methanol (20 mL).HCl (1N, 20 mL) was added and the reaction solvent removed in vacuo togive the product as a yellow solid (1.2 g, 78% yield). Alcohol (522 mg,0.92 mmol), trifluoroacetic anhydride (130 uL), methoxyethanol (4 mL)and methylene chloride (6 mL) were combined and heated to 70° C. for 18h. Additional trifluoroacetic anhydride (100 ul) was added and heatedfor 24 h. The reaction solvent was removed in vacuo and the solidtriturated with methanol to give the product as a yellow solid (325 mg,91% yield). A solution of the previous product (100 mg, 0.16 mmol) inmethylene chloride (3 mL)/methanol (1 mL)/hexamethylphosphoramide (500uL) was added cesium carbonate (212 mg, 0.65 mmol). The reaction mixturewas stirred at room temperature for 20 min. and acetaldehyde was addedand the mixture was stirred for 18 h. Additional cesium carbonate andacetaldehyde was added and the mixture stirred for 3 h. The mixture wasdiluted with methylene chloride, washed with water and brine, andpurified by flash chromatography on silica gel using ethylacetate/methylene chloride (10%) to give product (45 mg, 43% yield). Theproduct (45 mg) was dissolved in methylene chloride (4 mL) andethanethiol followed by trifluoroacetic anhydride was added at 0° C.After 1.5 h, the reaction solvent was removed in vacuo and the materialpurified by flash chromatography on silica gel using methanol/ethylacetate (10%) to give product (11 mg, 37% yield). MS (ESI): m/e 443(M+1)⁺.

Example 160

To the tritrifluoroacetate (27 mg) prepared using general method C wasadded 1 mL 2-methoxyethanol and the reaction was heated to 90° C. in asealed tube for 2 hours. The reaction was concentrated, the producttriturated with ether, collected and dried. ¹HNMR(400 MHz, DMSO) δ8.38(1H, s), 7.89 (2H, d), 7.66 (1H, d), 7.47(1H, d), 6.90(1H, s),6.81(1H, d), 4.98(2H,m), 4.79(1H, s), 4.67(3H, m), 3.96(6H, m),3.82((2H, m), 3.62 (2H, m), 3.50(3H, m), 3.10(2H, m), 2.79(2H, m) MS m/e487 (M+1)⁺

Example 161

To the amino methyl intermediate XII CEP7668 (30 mg, 0.066 mmol) in THF(1 mL) was added TEA (9 μl, 0.066 mmol), followed by benzylchloroformate (9 μl, 0.066 mmol) and the reaction mixture was stirred atroom temperature overnight. Additional TEA and benzyl chloroformate wereadded while heating to 50° C. The reaction was concentrated, dissolvedin ethyl acetated, washed with sodium bicarbonate, brine and dried overmagnesium sulfate. The drying agent was removed by filtration and thesolvent evaporated. The product was purified by preparative TLC using 2%methanol/methylene chloride. The product was collected and dried at 80°C. overnight. MS m/e=590 (m+1)⁺.

Example 162

This compound was prepared using the general procedure as Example 161starting with 3-aminomethyl-N-ethanol intermediate XIII MS m/e 540(m+1)⁺.

Example 163

This compound was prepared from XII intermediate and ethyl isocyanatoacetate. MS m/e 513 (m+1)⁺.

Example 164

Phenol intermediate X CEP 7143 (15 mg, 0.037 mmol), bromoethylethylether(66 mg., 0.57 mmol) (added in 3 portions), acetone (7 mL) and 10N sodiumhydroxide (4 mL.) were stirred at room temperature for 7 hr. The acetonewas evaporated and the solution acidified to pH 3. The solid wascollected, triturated with hexane and then extracted with methylenechloride. The extract was evaporated to give the product (0.004 g.)(23%) MS m/e 471 (M+1); ¹H-NMR (DMSO-d₆) 11.40 (s, 1H), 8.33 (s, 1H),8.16 (d, 1H), 7.47 (d, 2H), 7.11 (d, 1H), 6.86 (s, 1H), 6.78 (d, 1H),4.80 (s, 2H), 4.69 (m, 1H), 4.24 (m, 2H), 3.85 (m, 2H), 3.65 (t, 2H),2.98 (t, 2H), 2.81 (t, 2H), 1.30 (d, 6H), 1.23 (t, 3H).

Example 165

A mixture of intermediate X (16.5 mg, 0.041 mmol) and cesium carbonate(88 mg, 1.1 eq) in 2.0 mL of CH₃CN was added cyclopentyl bromide (8.0ul, 2.0 eq.) under N₂. After stirred at 70° C. for 24 hours, the mixturewas diluted with CH₂Cl₂ and filtered through celite and concentrated.Purification by preparation TLC plate with CH₂Cl₂/MeOH afforded theproduct. MS m/e 533 (M+1).

Example 166

Prepared by hydrogenation of Example 1C in DMF using Pd(OH)₂ and a dropof HCl. MS m/e 443 (M+1)

Example 1C

A suspension of sodium hydride (2.44 mg, 1.22 eq.) in 0.5 mL of THF wasstirred under N₂ as phenol intermediate X(3-hydroxy-10-isopropoxy-12,13-dihydro-6H,7H,14H-nephthyl(3,4-a)pyrrolo(3,3-a)pyrrolo(3,4-c)carbazole-7(7H)one)(20.6 mg, 0.05 mmol) in 2.0 mL of THF:DMF (1:1) was added dropwise.After 10 minutes of stirring, 2-bromopyrimidine (8.9 mg, 1.12 eq.) in0.5 mL of THF was added. The mixture was stirred at 60° C. for 14 hours.Then, the mixture was cooled to room temperature, diluted withCH₂Cl₂/MeOH, filtered through celite and concentrated. Purification wasachieved by preparation TLC plate with CH₂Cl₂/MeOH (9:1) to afford theproduct (4.0 mg, 17%) (MS: 477 m/z (M+H)⁺).

General Methods for Synthesis of Examples 167-191.

Method A: A mixture of hydroxyl intermediate (0.2 mmol), potassiumiodide (3.3 mg, 0.1 eq.), N-tetrabutylammonium bromide (0.1 eq), cesiumhydroxide hydrate (3 eq) and 20 mg of 4 Å sieves in 2.0 mL of CH₃CN wasadded the appropriate alkyl bromide or iodide under N₂. After themixture was stirred at 50° C. for 14-72 hours, the reaction mixture wasdiluted with CH₃CN and filtered through celite and concentrated. Theresidue was diluted with CH₂Cl₂ and washed with water and dried overmagnesium sulfate. Purification by preparation TLC plate orcrystallization with CH₂Cl₂/MeOH afforded the desired products.

Method B: A mixture of hydroxy intermediate (0.2 mmol) and cesiumcarbonate (3 eq) in 2.0 mL of CH₃CN was added the appropriate alkylbromide or iodide under N₂. After the mixture was stirred at 50-80° C.for 14-72 hours, the reaction mixture was diluted with CH₃CN andfiltered through celite and concentrated. The residue was diluted withCH₂Cl₂ and washed with water and dried over magnesium sulfate.Purification by preparation TLC plate or crystallization withCH₂Cl₂/MeOH afforded the desired product.

Method C: A mixture of hydroxyl intermediate (0.1 mmol), sodiumhydroxide (1.5 eq.) and N-tetrabutylammonium bromide (0.1 eq) in 0.5 mLof CH₂Cl₂ and 0.5 mL of water was added the appropriate alkyl bromideunder N₂. After the mixture was stirred at room temperature for 14-72hours, the reaction mixture was concentrated and the residue was washedwith water and dried over magnesium sulfate. Purification by preparationTLC plate with CH₂Cl₂/MeOH or crystallization afforded the desiredproduct.

Example 167

A mixture of intermediate phenol XV (19.5 mg, 0.05 mmol), potassiumcarbonate (34.6 mg, 5 eq.) and potassium iodide (8.7 mg, 1.05 eq) in 1.5mL of acetone and 0.25 mL of DMF was added the benzyl 2-bromoethyl ether(8.3 uL, 1.05 eq.) under N₂. After the mixture was stirred at reflux for24 hours, the reaction mixture was diluted with EtOAc and washed withwater, saturated NaCl solution and dried over magnesium sulfate.Purification by preparation TLC plate with 5% of MeOH/CH₂Cl₂ affordedthe desired product (10 mg, 39%). MS m/e 519 m/z (M+1)⁺.

Example 168

The product was obtained by first forming compound 168I by Method A,using phenol XV and cyclopentyl bromide; 14 hr; prep. TLC (10% MeOH inCH₂Cl₂); yield 10%; MS: m/e 453 m/z (M+1)⁺. A mixture of compound 168I110 (5 mg, 0.01 mmol), 10% Pd(OH)₂/C and 0.1 mL of conc. HCl in 1.0 mLof EtOH was hydrogenated under 42 psi H₂ on a Parr apparatus for 24hours at room temperature. Filtration and concentration afforded 2.2 mg(27%) of the title compound. MS: m/e 451 m/z (M+1)⁺.

Example 169

Method C from phenol XV and epibromohydrin; 22 hour, preparative TLC(10% MeOH in CH₂Cl₂); yield 30%; MS: m/e 463 m/z (M+Na)⁺.

Example 170

Method C; phenol XV and 1-bromo-2-(2-methoxyethoxy)ethane, 14 hr; prep.TLC (10% MeOH in CH₂Cl₂); yield 11%; MS: 509 m/z (M+Na)⁺.

Example 171

Method B; phenol XV and 2-(2-bromoethyl)-1,3-dioxane, 14 hr reflux;prep. TLC (10% MeOH in CH₂Cl₂); yield 54%; MS: 521 m/z (M+1)⁺.

Example 172

Method A; phenol XV and (bromomethyl)cyclopropane, 14 hr; prep. TLC (10%MeOH in CH₂Cl₂); yield 17%; MS: m/e 439 m/z (M+1)⁺.

Example 173

Method A; phenol XV and 2-bromomethyl-1,3-dioxolane; 64 hr; prep. TLC(10% MeOH in CH₂Cl₂); yield 15%; MS: 471 m/z (M+1)⁺.

Example 174

Method B; phenol XV and N-(3-bromopropyl)phthalimide; 48 hr at 80° C.;prep. TLC (10% MeOH in CH₂Cl₂); yield 17%; MS: m/e 494 m/z (M+Na)⁺.

Example 175

Method B; phenol XV and ethyl 2-bromopropionate; 14 hr at 80° C.; prep.TLC (10% MeOH in CH₂Cl₂); yield 9%; MS: m/e 507 m/z (M+Na)⁺.

Example 176

Method A; phenol XV and methyl 4-chloro-3-methoxy-(E)-2-butenoate; 40 hrat 80° C.; prep. TLC (10% MeOH in CH₂Cl₂); yield 21%; MS: m/e 535 m/z(M+Na)⁺.

Example 177

Method A; phenol XV and 1-bromopinacolone; 14 hr at 60° C.; prep. TLC(10% MeOH in CH₂Cl₂); yield 29%; MS: m/e 505 m/z (M+Na)⁺.

Example 178

Method A; 20 hr at 50° C.; prep. TLC (10% MeOH in CH₂Cl₂); yield (5%);MS: 449 m/z (M+Na)⁺.

Example 179

Method B. (38%) MS m/e 471 (M+1); ¹H-NMR (DMSO-d₆) 8.37 (s, 1H), 7.90(d, 1H), 7.83 (d, 1H), 7.64 (d, 1H), 7.46 (t, 1H), 7.25 (t, 1H), 6.86(s, 1H), 6.75 (d 1H), 4.97 (t, 1H), 4.77 (d, 4H), 4.60 (t, 2H), 4.16 (m,2H), 3.78 (m, 2H), 2.45 (s, 2H), 1.21 (t, 3H).

Example 180

Method B (19%) MS m/e 476 (M+1); ¹H-NMR (DMSO-d₆) 8.56 (s, 1H), 8.36 (s,1H), 7.92 (d, 1H), 7.85 (m, 2H), 7.66 (d, 1H), 7.51 (d, 2H), 7.48 (t,1H), 7.33 (m, 1H), 7.27 (t, 1H), 6.97 (s, 1H), 6.85 (d, 1H), 5.20 (s,1H), 4.97 (m, 1H), 4.75 (s, 2H), 4.62 (m, 2H).

Example 181

Method B (43%) MS m/e 443 (M+1); ¹H-NMR (DMSO-d₆) 8.36 (s, 1H), 7.90 (d,1 h), 7.83 (d, 1H), 7.64 (d, 1H), 7.45 (t, 1H), 7.24 (t, 1H), 6.87 (s,1H), 6.77 (d, 1H), 4.97 (t, 1H), 4.75 (s, 2H), 4.61 (s, 2H), 4.11 (s,2H), 3.77 (d, 2H), 3.65 (s, 2H), 2.73 (s, 2H).

Example 182

Method B (63%) MS m/e 452 (M+1); ¹H-NMR (DMSO-d₆) 8.36 (s, 1H), 7.90 (d,1H), 7.83 (d, 1H), 7.65 (d, 1H), 7.46 (t, 1H), 7.24 (t, 1H), 6.88 (s,1H), 6.78 (d, 1H), 4.96 (t, 1H), 4.75 (s,2H), 4.60 (m, 2H), 4.07 (t,2H), 3.78 (m, 2H), 2.74 (m, 2H), 2.64 (t, 2H), 2.02 (m, 2H).

Example 183

Method B (72%) MS m/e 480 (M+1); ¹H-NMR (DMSO-d₆) 8.35 (s, 1H), 7.91 (d,1H), 7.82 (d, 1H), 7.64 (d, 1H), 6.85 (t, 1H), 6.76 (t, 1H), 4.96 (t,1H), 4.75 (s, 2H), 4.60 (s,2H), 4.00 (t,2H), 3.77 (d, 2H), 2.73 (m, 2H),1.73 (t, 3H), 1.52 (m, 8H),

Example 184

Method B (67%) MS m/e 456 (M+1); ¹H-NMR (DMSO-d₆) 8.35 (s,1H), 7.91(d,1H), 7.83 (d,1H), 7.64 (d,1H), 7.46 (t,1H), 7.24 (t,1H), 6.87 (s,1H),6.75 (d,1H), 4.96 (t,1H), 4.75 (s,2H), 4.60 (t,2H), 4.10 (s,2H), 3.78(m,2H), 3.70 (s,2H), 3.00 (m,2H), 2.70 (m,2H), 1.11 (T,3 h).

Example 185

Method B (88%) MS m/e 466 (M+1); ¹H-NMR (DMSO-d₆) 8.35 (s, 1H), 7.91 (d,1H), 7.83 (d, 1H), 7.64 (d, 1H), 7.46 (t, 1H), 7.24 (t, 1H), 6.86 (s,1H), 6.77 (d, 1H), 4.96 (t, 1H), 4.75 (s, 2H), 4.61 (m, 2H), 4.03 (t,2H), 3.78 (m, 2H), 2.74 (m, 2H), 2.54), (t, 2H), 1.73 (m, 6H).

Example 186

Method B. MS m/e 516 (M+1); ¹H-NMR (DMSO-d₆) 8.35 (s, 1H), 7.90 (d, 1H),7.81 (d, 1H), 7.64 (d, 1H), 7.46 (t, 1H), 7.24 (t, 1H), 6.85 (s, 1H),6.76 (d, 1H), 4.96 (t, 1H), 4.75 (s, 2H), 4.60 (t, 2H), 3.99 (t, 2H),3.78 (m, 2H), 2.74 (m, 2H), 1.71 (m, 2H), 1.56 (t, 4H), 1.42 (m, 6H).

Example 187

Method B. MS m/e 438 (M+1).

Example 188

This compound was formed from Example 185B, ethanol and gaseous hydrogenchloride (85%) MS m/e 512 (M+1); ¹H-NMR (DMSO-d₆) 8.35 (s, 1H), 7.91 (s,1H), 7.83 (d, 1H), 7.65 (d, 1H), 7.46 (t, 1H), 7.26 (t, 1H),6.85 (s,1H), 6.76 (d, 1H), 4.75 (s, 1H), 4.61 (m, 2H), 4.35 (m, 2H), 4.00 (m,2H), 3.79 (m, 2H), 2.73 (m, 2H), 2.66 (m, 2H), 1.77 (m, 6H), 1.33 (t,3H).

Example 189

Example 188 was refluxed in ethanol and concentrated hydrochloric acidfor 18 hr. The solution was made basic with sodium hydroxide to pH 10and refluxed 4 hours. The solution was acidified to precipitate theproduct. MS m/e 485 (M+1); ¹H-NMR (DMSO-d₆) 12.00 (s, 1H), 7.91 (d, 1H),7.82 (d, 1H), 7.65 (d, 1H), 7.45 (t, 1H), 7.24 (m, 2H), 6.85 (s, 1H),6.76 (d, 2H), 4.96 (t, 1H), 4.75(s, 2H), 4.61 (m, 2H), 3.98 (t, 1H),3.77 (m, 2H), 2.73(m, 2H), 2.23 (m, 4H), 1.71(m, 8H).

Example 190

The product was obtained from a reaction of Example 186 with ethanol andgaseous hydrogen chloride (45%) MS m/e 512 (M+1); ¹H-NMR (DMSO-d₆) 8.37(s, 1H), 7.91 (d, 1H), 7.82 (d, 1H), 7.65 (d, 1H), 7.47 (t, 1H), 7.23(m, 2H), 6.86 (s, 1H), 6.77 (d, 2H), 6.67 (s, 1H), 4.99 (t, 1H), 4.76(s, 2H), 4.61 (m, 2H), 3.98 (t, 1H), 3.80 (m, 2H), 2.74 (m, 2H), 2.02(t, 2H), 1.71 (m, 2H), 1.38 (m, 8H).

Synthesis of intermediate phenol XVII CEP 5108: To aluminum trichloride(1.2 g, 9 mmol) in 12 mL anhydrous dichloroethane was added 2 mLethanethiol followed by methoxy derivative CEP 3371 (500 mg, 1.47 mmol).The mixture was stirred at 50° C. for 48 h. The reaction wasconcentrated and stirred with 10 mL 1N hydrochloric acid for thirtyminutes. The product was isolated by filtration and was dried in vacuoto afford 483 mg (quantitative) of a grey solid, the phenol. NMR(d₆-DMSO): 11.8 (s, 1H), 9.53 (s, 1H), 9.2 (d, 1H), 8.45 (s, 1H), 7.95(s, 1H), 7.6 (d, 1H), 7.45 (dd, 1H), 7.25 (dd, 1H), 7.08 (s, 1H), 6.8(dd, 1H), 4.85 (s, 2H), 4.08 (s, 2H). MS (ES+): 327 (M+1).

Example 191 and Example 192

Phenol intermediate XVII (25 mg, 79 μmole), potassium carbonate (17 mg,123 μmole), and ethyl bromoacetate (17 μL, 155 μmole) were combined in10 mL dry acetone. A drop of N,N-dimethylformamide was and the mixturewas heated at 50° C. for three days. HPLC analysis revealed the presenceof two products. The two products were separated employing reverse phaseC8 high performance liquid chromatography (1:1 acetonitrile:water with0.1% trifluoroacetic acid). The first product eluted was identified asthe mono adduct Example 191B. 2 mg. NMR (d₆-DMSO): 11.7 (s, 1H), 9.25(d, 1H), 8.5 (s, 1H), 7.95 (d, 1H), 7.60 (d, 1H), 7.45 (dd, 1H),7.25-7.3 (m, 2H), 7.0 (dd, 1H), 4.93 (s, 2H), 4.85 (s, 2H), 4.22 (q,2H), 4.15 (s, 2H), 1.20 (t, 3H). MS (ES+): 435 (M+Na). Retention time:13.03 min (gradient elution 10%-95% acetonitrile:water (0.1%trifluoroacetic acid) at 1.6 mL/min on a Zorbax RX-C8 4.6 by 150 mmcolumn). The second product eluted was identified as the bis adductExample 192B. NMR (d₆-DMSO): 8.3 (d, 1H), 8.06 (s, 1H), 7.96 (d, 1H),7.72 (d, 1H), 7.45 (dd, 1H), 7.27 (dd, 1H), 7.20 (br s, 1H), 6.95 (dd,1H), 5.6 (s, 2H), 5.42 (s, 2H), 5.35 (s, 2H), 4.25 (s, 2H), 4.18 (q,2H), 3.75 (q, 2H), 1.2 (m, 6H). 2 mg. MS (ES+): 521 (M+Na).

Example 193

Prepared by the method described for Example 192 from bromoacetonitrile:NMR (d₆-DMSO): 11.85 (s, 1H), 9.3 (d, 1H), 8.48 (s, 1H), 7.95 (d, 1H),7.58 (d, 1H), 7.4 (m, 2H), 7.2 (dd, 1H), 7.1 (d, 1H), 5.2 (s, 2H), 4.85(s, 2H), 4.18 (s, 2H). MS (ES +): 366 (M+1).

Example 194

Example 192 (10 mg, 24 μmol) in 10 mL dry tetrahydrofuran was treatedwith lithium borohydride (0.5 mL of a 2.0 M solution in tetrahydrofuran,1.0 mmol) and heated at 40° C. for 72 h. 1 mL water was then added andthe solution was concentrated. The crude solid was taken up into 1 mLDMF and concentrated onto 600 mg silica. The silica was applied to thetop of a bed of silica and medium pressure liquid chromatography waseffected eluting with 4% methanol:dichloromethane to afford 3.0 mg of atan solid. NMR (d₆-DMSO): 11.8 (s, 1H), 9.2 (d, 1H), 8.45 (s, 1H), 7.92(d, 1H), 7.55 (d, 1H), 7.41 (dd, 1H), 7.25 (m, 2H), 6.95 (dd, 1H), 4.85(s, 2H), 4.08 (s, 2H), 4.06 (m, 2H), 3.75 (m, 2H), 3.56 (t, 1H). MS(ES+): 371 (M+1).

Example 195

This compound was prepared by the method described for Example 194 fromExample 193: NMR (d₆-DMSO): 9.3 (d, 1H), 8.48 (s, 1H), 7.95 (d, 1H),7.70 (d, 1H), 7.45 (dd, 1H), 7.28 (m, 1H), 7.22 (s, 1H), 6.95 (d, 1H),4.9 (s, 2H), 4.7 (br s, 2H), 4.46 (s, 2H), 4.06 (br s, 2H), 3.80 (br s,2H), 3.70 (br s, 2H), 3.52 (overlapping s, 2H). MS (ES+): 415 (M+1).

Example 196

The O-allyl intermediate was prepared using allyl bromide as describedfor Example 194: NMR (d₆-DMSO): 11.8 (s, 1H), 9.27 (d, 1H), 8.48 (s,1H), 7.98 (d, 1H), 7.60 (d, 1H), 7.45 (dd, 1H), 7.30 (s, 1H), 7.25 (m,1H), 7.05 (dd, 1H), 6.10 (m, 1H), 5.4 (dd, 1H), 5.3 (dd, 1H), 4.95 (s,2H), 4.7 (d, 2H), 4.18 (s, 2H). MS (ES+): 367 (M+1). IntermediateO-allyl (20 mg, 55,mol), osmium tetroxide (0.1 mL of a 25 mg/mL solutionin carbon tetrachloride), N-methylmorpholine-N-oxide (50 mg) werecombined in 10 mL tetrahydrofuran to which was added 0.1 mL water. Themixture was stirred in the dark for 48 h. The mixture was concentratedonto 0.6 g silica and applied to a bed of silica. Medium pressure liquidchromatography eluting with 5% methanol:dichloromethane afforded 23 mgof a yellow solid. NMR (d₆ DMSO): 11.8 (s, 1H), 9.23 (d, 1H), 8.43 (s,1H), 7.92 (d, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 7.25 (s, 1H), 7.22 (m,1H), 6.95 (d, 1H), 4.95 (d, 1H), 4.88 (s, 2H), 7.70 (dd, 1H), 4.10 (s,2H), 4.05 (d, 1H), 3.7-3.95 (m, 4H). MS (ES+): 401 (M+1).

Example 197

Example 194 (63 mg, 153 μmol), dimethylamine (3 mL of a 40% solution inwater), and ammonium chloride (100 mg) were combined inN,N-dimethylformamide and stirred at ambient temperature in a sealedtube for 5 d. The solution was concentrated onto 0.6 g silica andapplied to a bed of silica. Medium pressure liquid chromatographyemploying a gradient from 5-10% methanol:dichloromethane afforded 60 mgof an orange solid. NMR (d₆-DMSO): 11.80 (s, 1H), 9.20 (d, 1H), 8.45 (s,1H), 7.95 (d, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 7.2-7.28 (m, 2H), 6.93(d, 1H), 4.90 (s, 2H), 4.82 (s, 2H), 4.05 (s, 2H), 3.0 (s, 3H), 2.83 (s,3H). MS (ES+): m/e 434 (M+Na).

Example 198

The epoxide (42 mg, 0.11 mmol), dimethylamine (3 mL of a 40% solution inwater), and ammonium chloride (100 mg) were combined in 10 mLN,N-dimethylformamide and stirred in a sealed tube for 16 h. The mixturewas concentrated onto 700 mg silica and applied to a bed of silica.Medium pressure liquid chromatography employing a gradient of 15-25%methanol:dichloromethane afforded approximately 5 mg of the polardesired. NMR (d₆-DMSO): 12.1 (br s, 1H), 9.55 (d, 1H), 8.45-8.52 (m,2H), 7.72 (d, 1H), 7.65 (dd, 1H), 7.35-7.5 (m, 2H), 7.15 (d, 1H), 5.75(s, 2H), 5.18 (s, 2H), 4.15-4.35 (m, 4H), 2.70 (m, 1H), 2.55 (s, 6H),2.50 (m, 1H). MS (ES+): m/e 428 (M+1).

Example 199

This compound was prepared by the same procedure as Example 198 usingmorpholine: MS (ES+): m/e 470 (M+1).

Utility

The compounds of the present invention are useful, inter alia, astherapeutic agents. Particularly, the compounds are useful for kinaseinhibition, such as, for example, trk, VEGFR, PDGFR, PKC, MLK, DLK,Tie-2, FLT-3, and CDK1-6. Various compounds of the present inventionshow enhanced pharmaceutical properties over those disclosed in the artand improved pharmacokinetic properties in mammals. The compounds of thepresent invention show enhanced pharmaceutical properties over thosedisclosed in the art, including increased MLK and DLK dual inhibitionactivity, or increased VEGFR and Tie-2 dual inhibition activity, alongwith improved pharmacokinetic properties in mammals.

In one embodiment, the present invention provides a method for treatingor preventing diseases and disorders, such as those disclosed herein,which comprises administering to a subject in need of such treatment orprevention a therapeutically effective amount of a compound of thepresent invention.

In an additional embodiment, the present invention provides a method forinhibiting trk kinase activity comprising providing a compound of thepresent invention in an amount sufficient to result in effectiveinhibition. Particularly, inhibition of trk implies utility in, forexample, diseases of the prostate such as prostate cancer and benignprostate hyperplasia, as well as for the treatment of inflammation, suchas neurological inflammation and chronic arthritis inflammation. In apreferred embodiment, the trk kinase receptor is trk A.

The majority of cancers have an absolute requirement for angiogenesis,the process by which new blood vessels are formed. The most potentangiogenic cytokine is vascular endothelial growth factor (VEGF) andthere has been substantial research into the development of VEGF/VEGFreceptor (VEGFR) antagonists. Receptor tyrosine kinase (RTK) inhibitorscould have broad spectrum antitumor activity in patients with advancedpre-treated breast and colorectal carcinoma and Kaposi's sarcoma.Potentially these agents may play a role in the treatment of both early(adjuvant) and advanced cancer. The importance of angiogenesis for theprogressive growth and viability of solid tumors is well established.Emerging data suggest an involvement of angiogenesis in thepathophysiology of hematologic malignancies as well. Recently, authorshave reported increased angiogenesis in the bone marrow of patients withacute myeloid leukemia (AML) and normalization of bone marrowmicrovessel density when patients achieved a complete remission (CR)after induction chemotherapy. Tumor angiogenesis depends on theexpression of specific mediators that initiate a cascade of eventsleading to the formation of new microvessels. Among these, VEGF(vascular endothelial growth factor), FGF (fibroblast growth factor)play a pivotal role in the induction of neovascularization in solidtumors. These cytokines stimulate migration and proliferation ofendothelial cells and induce angiogenesis in vivo. Recent data suggestan important role for these mediators in hematologic malignancies aswell. Isolated AML blasts overexpress VEGF and VEGF receptor 2. Thus,the VEGF/VEGFR-2 pathway can promote the growth of leukemic blasts in anautocrine and paracrine manner. Therefore, neovascularization andangiogenic mediators/receptors may be promising targets foranti-angiogenic and anti-leukemic treatment strategies. Thus, in otherembodiments, the present invention provides a method for treating orpreventing angiogenic disorders where VEGFR kinase activity contributesto pathological conditions, the method comprising providing a compoundof the present invention in an amount sufficient to result in thevascular endothelial growth factor receptor being contacted with aneffective inhibitory amount of the compound. Inhibition of VEGFR impliesutility in, for example, angiogenic disorders such as cancer of solidtumors, endometriosis, macular degeneration, retinopathy, diabeticretinopathy, psoriasis, hemangioblastoma, as well as other oculardiseases and cancers.

FLT3, a member of the receptor tyrosine kinase (RTK) class III, ispreferentially expressed on the surface of a high proportion of acutemyeloid leukemia (AML) and B-lineage acute lymphocytic leukemia (ALL)cells in addition to hematopoietic stem cells, brain, placenta andliver. An interaction of FLT3 and its ligand has been shown to play animportant role in the survival, proliferation and differentiation of notonly normal hematopoetic cells but also leukemia cells. Mutations of theFLT3 gene was first reported as an internal tandem duplication (ITD) ofthe juxtamembrane (JM) domain-coding sequence, subsequently as amissense mutation of D835 within a kinase domain. ITD- andD835-mutations are essentially found in AML and their frequencies areapproximately 20 and 6% of adults with AML, respectively. Thus, mutationof the FLT3 gene is so far the most frequent genetic alteration reportedto be involved in AML. Several large-scale studies in well-documentedpatients published to date have demonstrated that ITD-mutation isstrongly associated with leukocytosis and a poor prognosis. An inhibitorcompound of FLT3 tyrosine kinase have an application in treatment ofleukemia. The present invention provides a method for treating disorderscharacterized by responsiveness to FLT3 inhibition, the methodcomprising providing a compound of the present invention in an amountsufficient to result in the inhibition of FLT3.

Platelet-derived growth factor (PDGF) was one of the first polypeptidegrowth factors identified that signals through a cell surface tyrosinekinase receptor (PDGF-R) to stimulate various cellular functionsincluding growth, proliferation, and differentiation. Since then,several related genes have been identified constituting a family ofligands (primarily PDGF A and B) and their cognate receptors (PDGF-Ralpha and beta). To date, PDGF expression has been shown in a number ofdifferent solid tumors, from glioblastomas to prostate carcinomas. Inthese various tumor types, the biologic role of PDGF signaling can varyfrom autocrine stimulation of cancer cell growth to more subtleparacrine interactions involving adjacent stroma and even angiogenesis.Thus, in additional embodiments, the present invention provides a methodfor treating or preventing disorders where PDGFR activity contributes topathological conditions, the method comprising providing a compound ofthe present invention in an amount sufficient to result in the plateletderived growth factor receptor being contacted with an effectiveinhibitory amount of the compound. Inhibition of PDGFR implies utilityin, for example, various forms of neoplasia, rheumatoid arthritis,chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal woundhealing, diseases with cardiovascular end points, such asatherosclerosis, restenosis, post-angioplasty restenosis, and the like.

In further embodiments, the present invention provides a method fortreating or preventing disorders where MLK activity contributes topathological conditions, such as those listed above, wherein the methodcomprises providing a compound of the present invention in an amountsufficient to result in the MLK receptor being contacted with aneffective inhibitory amount of the compound. Inhibition of MLK impliesutility in, for example, forms of cancer where MLKs play a pathologicalrole as well as in neurological disorders.

In still other embodiments, the present invention provides a method fortreating disorders characterized by the aberrant activity of trophicfactor responsive cells, the method comprising providing a compound ofthe present invention in an amount sufficient to result in the trophicfactor cell receptor being contacted with an effective activity inducingamount of the compound. In certain preferred embodiments, the activityof the trophic factor responsive cells is ChAT activity.

Fibroblast growth factor receptors (FGFR) are members of a family ofpolypeptides synthesized by a variety of cell types during the processesof embryonic development and in adult tissues. FGFR have been detectedin normal and malignant cells and are involved in biological events thatinclude mitogenic and angiogenic activity with a consequent crucial rolein cell differentiation and development. To activate signal transductionpathways, FGFR are coupled to fibroblast growth factors (FGF) andheparan sulfate (HS) proteoglycans to form a biologically fundamentalternary complex. Based on these considerations, inhibitors able to blockthe signaling cascade through a direct interaction with FGFR could haveantiangiogenesis and subsequent antitumor activity. Accordingly, thepresent invention provides a method for treating disorders characterizedby the aberrant activity of FGF responsive cells, the method comprisingproviding a compound of the present invention in an amount sufficient toresult in the FGFR being contacted with an effective activity inducingamount of the compound.

The compounds of the present invention can also have positive effects onthe function and survival of trophic factor responsive cells bypromoting the survival of neurons. With respect to the survival of acholinergic neuron, for example, the compound may preserve the survivalof a cholinergic neuronal population at risk of dying (due to, e.g.,injury, a disease condition, a degenerative condition or naturalprogression) when compared to a cholinergic neuronal population notpresented with such compound, if the treated population has acomparatively greater period of functionality than the non-treatedpopulation.

A variety of neurological disorders are characterized by neuronal cellswhich are dying, injured, functionally compromised, undergoing axonaldegeneration, at risk of dying, etc. These neurodegenerative diseasesand disorders include, but are not limited to, Alzheimer's disease;motor neuron disorders (e.g. amyotrophic lateral sclerosis); Parkinson'sdisease; cerebrovascular disorders (e.g., stroke, ischemia);Huntington's disease; AIDS dementia; epilepsy; multiple sclerosis;peripheral neuropathies including diabetic neuropathy and chemotherapyinduced peripheral neuropathy, AID related peripheral neuropathy;disorders induced by excitatory amino acids; and disorders associatedwith concussive or penetrating injuries of the brain or spinal cord.

In other preferred embodiments, the compounds of the present inventionare useful for treating or preventing multiple myeloma and leukemiasincluding, but not limited to, acute myelogenous leukemia, chronicmyelogenous leukemia, acute lymphocytic leukemia, and chroniclymphocytic leukemia.

In additional embodiments, the present compounds are also useful in thetreatment of disorders associated with decreased ChAT activity or thedeath, injury to spinal cord motoneurons, and also have utility in, forexample, diseases associated with apoptotic cell death of the centraland peripheral nervous system, immune system and in inflammatorydiseases. ChAT catalyzes the synthesis of the neurotransmitteracetylcholine, and it is considered an enzymatic marker for a functionalcholinergic neuron. A functional neuron is also capable of survival.Neuron survival is assayed by quantification of the specific uptake andenzymatic conversion of a dye (e.g., calcein AM) by living neurons. Thecompounds described herein may also find utility in the treatment ofdisease states involving malignant cell proliferation, such as manycancers.

The compounds of the present invention have important functionalpharmacological activities which find utility in a variety of settings,including both research and therapeutic arenas. For ease ofpresentation, and in order not to limit the range of utilities for whichthese compounds can be characterized, the activities of the compounds ofthe present invention can be generally described as follows:

A. Inhibition of Enzymatic Activity

B. Effect on the Function and/or Survival of Trophic Factor ResponsiveCells

C. Inhibition of Inflammation-associated Responses

D. Inhibition of Cell Growth Associated with Hyperproliferative States

E. Inhibition of Developmentally Programmed Motoneuron Death

Inhibition of enzymatic activity can be determined using, for example,VEGFR inhibition (e.g., VEGFR2 inhibition), MLK inhibition (e.g., MLK1,MLK2 or MLK3 inhibition), PDGFR kinase inhibition, NGF-stimulated trkphosphorylation, PKC inhibition, or trk tyrosine kinase inhibitionassays. Effect on the function and/or survival of trophic factorresponsive cells, e.g., cells of a neuronal lineage, can be establishedusing any of the following assays: (1) cultured spinal cord cholineacetyltransferase (“ChAT”) assay; (2) cultured dorsal root ganglion(“DRG”) neurite extension assay; (3) cultured basal forebrain neuron(“BFN”) ChAT activity assay. Inhibition of inflammation-associatedresponse can be established using an indoleamine 2,3-dioxygenase (“IDO”)mRNA assay. Inhibition of cell growth associated with hyperproliferativestates can be determined by measuring the growth of cell lines ofinterest, such as an AT2 line in the case of prostate cancer. Inhibitionof developmentally programmed motoneuron death can be assessed in ovousing embryonic chick somatic motoneurons, which cells undergo naturallyoccurring death between embryonic days 6 and 10, and analyzinginhibition of such naturally occurring cell death as mediated by thecompounds disclosed herein.

The inhibition of enzymatic activity by the compounds of the presentinvention can be determined using, for example, the following assays:

VEGFR Inhibition Assay

MLK Inhibition Assay

PKC Activity Inhibition Assay

trkA Tyrosine Kinase Activity Inhibition Assay

Tie-2 Inhibition Assay

CDK1-6 Inhibition Assay

Inhibition of NGF-stimulated trk Phosphorylation in a Whole CellPreparation

Platelet Derived Growth Factor Receptor (PDGFR) Inhibition Assay

A description of assays that may be used in connection with the presentinvention are set forth below. They are not intended, nor are they to beconstrued, as limiting the scope of the disclosure.

Inhibition of trkA Tyrosine Kinase Activity

Selected compounds of the present invention were tested for theirability to inhibit the kinase activity of baculovirus-expressed humantrkA cytoplasmic domain using an ELISA-based assay as previouslydescribed (Angeles et al., Anal. Biochem. 236: 49-55, 1996). Briefly,the 96-well microtiter plate was coated with substrate solution(recombinant human phospholipase C-γ1/glutathione S-transferase fusionprotein (Rotin et al., EMBO J., 11: 559-567, 1992). Inhibition studieswere performed in 100 μl assay mixtures containing 50 mM Hepes, pH 7.4,40 μM ATP, 10 mM MnCl₂, 0.1% BSA, 2% DMSO, and various concentrations ofinhibitor. The reaction was initiated by addition of trkA kinase andallowed to proceed for 15 minutes at 37° C. An antibody tophosphotyrosine (UBI) was then added, followed by a secondaryenzyme-conjugated antibody, alkaline phosphatase-labelled goatanti-mouse IgG (Bio-Rad). The activity of the bound enzyme was measuredvia an amplified detection system (Gibco-BRL). Inhibition data wereanalyzed using the sigmoidal dose-response (variable slope) equation inGraphPad Prism. The concentration that resulted in 50% inhibition ofkinase activity is referred to as “IC₅₀”.

Inhibition of Vascular Endothelial Growth Factor Receptor KinaseActivity

Selected compounds of the present invention were examined for theirinhibitory effects on the kinase activity of baculovirus-expressed VEGFreceptor (human flk-1, KDR, VEGFR2) kinase domain using the proceduredescribed for the trkA kinase ELISA assay described above. The kinasereaction mixture, consisting of 50 mM Hepes, pH 7.4, 40 μM ATP, 10 mMMnCl₂, 0.1% BSA, 2% DMSO, and various concentrations of inhibitor, wastransferred to PLC-γ/GST-coated plates. VEGFR kinase was added and thereaction was allowed to proceed for 15 min. at 37° C. Detection ofphosphorylated product was accomplished by addition ofanti-phosphotyrosine antibody (UBI). A secondary enzyme-conjugatedantibody was delivered to capture the antibody-phosphorylated PLC-γ/GSTcomplex. The activity of the bound enzyme was measured via an amplifieddetection system (Gibco-BRL). Inhibition data were analyzed using thesigmoidal dose-response (variable slope) equation in GraphPad Prism.

Inhibition of Mixed Lineage Kinase-1 Activity

The kinase activity of MLK1 was assessed using the Millipore MultiscreenTCA “in-plate” format as described for protein kinase C (Pitt & Lee, J.Biomol. Screening, 1: 47-51, 1996). Briefly, each 50-μl assay mixturecontained 20 mM Hepes, pH 7.0, 1 mM EGTA, 10 mM MgCl₂, 1 mM DTT, 25 mMβ-glycerophosphate, 60 μM ATP, 0.25 μCi [γ-³²P]ATP, 0.1% BSA, 500 μg/mlmyelin basic protein (UBI #13-104), 2% DMSO, 1 μM of test compound, and1 μg/ml of baculoviral GST-MLK1_(KD). Samples were incubated for 15 minat 37° C. The reaction was stopped by adding ice cold 50% TCA and theproteins were allowed to precipitate for 30 min at 4° C. The plates werethen washed with ice cold 25% TCA. Supermix scintillation cocktail wasadded, and the plates were allowed to equilibrate for 1-2 hours prior tocounting using the Wallace MicroBeta 1450 PLUS scintillation counter.

Dual Leucine Zipper Bearing Kinase Assay

Compounds were tested for their ability to inhibit the kinase activityof recombinant baculoviral human DLK, containing the kinase domain andleucine zipper. Activity was measured in 384-well FluoroNunc plates(Cat#460372) using a time-resolved fluorescence readout (PerkinElmerApplication Note 1234-968). Plates were coated with 30 μl of the proteinsubstrate MKK7 (Merritt et al. 1999) at a concentration of 20 μg/ml inTris buffered saline (TBS). Each 30 μl assay contained 20 mM MOPS (pH7.2), 15 mM MgCl₂, 0.1 mM Na₃VO₄, 1 mM DTT, 5 mM EGTA, 25 mMβ-glycerophosphate, 0.1% BSA, 100 μM ATP, and 2.5% DMSO. Reactions werestarted by the addition of 10 ng/ml GST-hDLK_(KD/LZ). For IC₅₀determinations, a 10-point dose response curve was generated for eachcompound. Plates were incubated at 37° C. for 30 minutes, and thereactions stopped by the addition of 100 mM EDTA. Product was detectedusing Europium-labeled anti-phosphothreonine (Wallac#AD0093; diluted1:10000 in 3% BSA/T-TBS). Following overnight capture at 4° C., 50 μlenhancement solution (Wallac #1244-105) was added and the plate gentlyagitated for 5 min. The fluorescence of the resulting solution was thenmeasured using the time-resolved fluorescence (TRF) mode in theMultilabel Reader (Victor2 Model # 1420-018 or Envision Model # 2100).Inhibition data was analyzed using GraphPad PRISM. See also Merritt, S.E., Mata, M., Nihalani, D., Zhu, C., Hu, X., and Holzman, L. B. (1999)The Mixed Lineage Kinase DLK utilizes MKK7 and not MKK4 as Substrate. J.Biol. Chem. 274, 10195-10202.

Tie-2 Tyrosine Kinase Assay

Compounds were tested for their ability to inhibit the kinase activityof recombinant baculoviral human His₆-Tie2 cytoplasmic domain using amodification of the ELISA described for trkA (Angeles et al., 1996). A384-well plate format was used for single-point screening while IC₅₀swere performed on 96-well plates. For single-point screening, eachbarcoded 384-well Costar High Binding plate (Cat # 3703) was coated with50 μl/well of 10 μg/ml substrate solution (recombinant human GST-PLC-γ;Rotin et al., 1992) in Tris-buffered saline (TBS). The Tie2 activity wasmeasured in 50-μl assay mixtures containing 50 mM HEPES (pH 7.2), 40 μMATP, 10 mM MnCl₂, 2.5% DMSO, 0.05% BSA, and 200 ng/ml His₆-Tie2_(CD).For IC₅₀ determinations, the assays were run as described above but in96-well Costar High Binding plates (Cat # 3703) and with the volumesdoubled. A 10-point dose response curve was generated for each compound.The kinase reaction was allowed to proceed at 37° C. for 20 minutes. Thedetection antibody, N1-Eu anti-phosphotyrosine (PT66) antibody (Wallac#AD0041), was added at 1:2000 diluted in block buffer [3% BSA in TBSwith 0.05% Tween-20 (TBST)]. After one-hour incubation at 37° C., 50 μlof enhancement solution (Wallac #1244-105) was added and the plate wasgently agitated. The fluorescence of the resulting solution was thenmeasured using the time-resolved fluorescence (TRF) mode in theMultilabel Reader (Victor2 Model # 1420-018 or Envision Model # 2100).Inhibition data were analyzed using ActivityBase and IC₅₀ curves weregenerated using XLFit. The cited references are as follows:

-   -   1. Angeles, T. S., Steffler, C., Bartlett, B. A., Hudkins, R.        L., Stephens, R. M., Kaplan, D. R., and Dionne, C. A. (1996)        Enzyme-linked immunosorbent assay for trkA tyrosine kinase        activity. Anal. Biochem. 236, 49-55.    -   2. Rotin, D., Margolis, B., Mohammadi, M., Daly, R. J., Daum,        G., Li, N., Fischer, E. H., Burgess, W. H., Ullrich, A.,        Schlessinger, J. (1992) SH2 domains prevent tyrosine        dephosphorylation of the EGF receptor: identification of Tyr992        as the high-affinity binding site for SH2 domains of        phospholipase C-γ. EMBO J. 11, 559-567.        Dosage and Formulation

For therapeutic purposes, the compounds of the present invention can beadministered by any means that results in the contact of the activeagent with the agent's site of action in the body of the subject. Thecompounds may be administered by any conventional means available foruse in conjunction with pharmaceuticals, either as individualtherapeutic agents or in combination with other therapeutic agents, suchas, for example, analgesics. The compounds of the present invention arepreferably administered in therapeutically effective amounts for thetreatment of the diseases and disorders described herein to a subject inneed thereof.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques. The effective dose will vary depending upon anumber of factors, including the type and extent of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected, theformulation of the active agent with appropriate excipients, and theroute of administration. Typically, the compounds are administered atlower dosage levels, with a gradual increase until the desired effect isachieved.

Typical dose ranges are from about 0.01 mg/kg to about 100 mg/kg of bodyweight per day, with a preferred dose from about 0.01 mg/kg to 10 mg/kgof body weight per day. A preferred daily dose for adult humans includesabout 25, 50, 100 and 200 mg, and an equivalent dose in a human child.The compounds may be administered in one or more unit dose forms. Theunit dose ranges from about 1 to about 500 mg administered one to fourtimes a day, preferably from about 10 mg to about 300 mg, two times aday. In an alternate method of describing an effective dose, an oralunit dose is one that is necessary to achieve a blood serum level ofabout 0.05 to 20 μg/ml in a subject, and preferably about 1 to 20 μg/ml.

The compounds of the present invention may be formulated intopharmaceutical compositions by admixture with one or morepharmaceutically acceptable excipients. The excipients are selected onthe basis of the chosen route of administration and standardpharmaceutical practice, as described, for example, in Remington: TheScience and Practice of Pharmacy, 20^(th) ed.; Gennaro, A. R., Ed.;Lippincott Williams & Wilkins: Philadelphia, Pa., 2000. The compositionsmay be formulated to control and/or delay the release of the activeagent(s), as in fast-dissolve, modified-release, or sustained-releaseformulations. Such controlled-release, or extended-release compositionsmay utilize, for example biocompatible, biodegradable lactide polymers,lactide/glycolide copolymers, polyoxyethylene-polyoxypropylenecopolymers, or other solid or semisolid polymeric matrices known in theart.

The compositions can be prepared for administration by oral means;parenteral means, including intravenous, intramuscular, and subcutaneousroutes; topical or transdermal means; transmucosal means, includingrectal, vaginal, sublingual and buccal routes; ophthalmic means; orinhalation means. Preferably the compositions are prepared for oraladministration, particularly in the form of tablets, capsules or syrups;for parenteral administration, particularly in the form of liquidsolutions, suspensions or emulsions; for intranasal administration,particularly in the form of powders, nasal drops, or aerosols; or fortopical administration, such as creams, ointments, solutions,suspensions aerosols, powders and the like.

For oral administration, the tablets, pills, powders, capsules, trochesand the like can contain one or more of the following: diluents orfillers such as starch, or cellulose; binders such as microcrystallinecellulose, gelatins, or polyvinylpyrrolidones; disintegrants such asstarch or cellulose derivatives; lubricants such as talc or magnesiumstearate; glidants such as colloidal silicon dioxide; sweetening agentssuch as sucrose or saccharin; or flavoring agents such as peppermint orcherry flavoring. Capsules may contain any of the afore listedexcipients, and may additionally contain a semi-solid or liquid carrier,such as a polyethylene glycol. The solid oral dosage forms may havecoatings of sugar, shellac, or enteric agents. Liquid preparations maybe in the form of aqueous or oily suspensions, solutions, emulsions,syrups, elixirs, etc., or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assurfactants, suspending agents, emulsifying agents, diluents, sweeteningand flavoring agents, dyes and preservatives.

The compositions may also be administered parenterally. Thepharmaceutical forms acceptable for injectable use include, for example,sterile aqueous solutions, or suspensions. Aqueous carriers includemixtures of alcohols and water, buffered media, and the like. Nonaqueoussolvents include alcohols and glycols, such as ethanol, and polyethyleneglycols; oils, such as vegetable oils; fatty acids and fatty acidesters, and the like. Other components can be added includingsurfactants; such as hydroxypropylcellulose; isotonic agents, such assodium chloride; fluid and nutrient replenishers; electrolytereplenishers; agents which control the release of the active compounds,such as aluminum monostearate, and various co-polymers; antibacterialagents, such as chlorobutanol, or phenol; buffers, and the like. Theparenteral preparations can be enclosed in ampules, disposable syringesor multiple dose vials. Other potentially useful parenteral deliverysystems for the active compounds include ethylene-vinyl acetatecopolymer particles, osmotic pumps, implantable infusion systems, andliposomes.

Other possible modes of administration include formulations forinhalation, which include such means as dry powder, aerosol, or drops.They may be aqueous solutions containing, for example,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oilysolutions for administration in the form of nasal drops, or as a gel tobe applied intranasally. Formulations for topical use are in the form ofan ointment, cream, or gel. Typically these forms include a carrier,such as petrolatum, lanolin, stearyl alcohol, polyethylene glycols, ortheir combinations, and either an emulsifying agent, such as sodiumlauryl sulfate, or a gelling agent, such as tragacanth. Formulationssuitable for transdermal administration can be presented as discretepatches, as in a reservoir or microreservoir system, adhesivediffusion-controlled system or a matrix dispersion-type system.Formulations for buccal administration include, for example lozenges orpastilles and may also include a flavored base, such as sucrose oracacia, and other excipients such as glycocholate. Formulations suitablefor rectal administration are preferably presented as unit-dosesuppositories, with a solid based carrier, such as cocoa butter, and mayinclude a salicylate.

As those skilled in the art will appreciate, numerous modifications andvariations of the present invention are possible in light of the aboveteachings. It is therefore understood that within the scope of theappended claims, the invention may be practiced otherwise than asspecifically described herein, and the scope of the invention isintended to encompass all such variations.

1. A compound of Formula I:

wherein: ring A together with the carbon atoms to which it is attached,is a phenylene ring in which from 1 to 3 carbon atoms may be replaced bynitrogen atoms; A¹ and A² are independently selected from H, H; and agroup wherein A¹ and A² together form a moiety selected from ═O; B¹ andB² are independently selected from H, H; and a group wherein B¹ and B²together form a moiety selected from ═O; provided that at least one ofthe pairs A¹ and A², or B¹ and B² forms ═O; R¹ is H or optionallysubstituted alkyl, wherein said optional substituents are one to threeR¹⁰ groups; R² is selected from H, C(═O)R^(2a), C(═O)NR^(2c)R^(2d),SO₂R^(2b), CO₂R^(2b), optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted cycloalkyl, and optionally substituted heterocycloalkyl,wherein said optional substituents are one to three R¹⁰ groups; R^(2a)is selected from optionally substituted alkyl, optionally substitutedaryl, OR^(2b), NR^(2c)R^(2d), (CH₂)_(p)NR^(2c)R^(2d), andO(CH₂)_(p)NR^(2c)R^(2d), wherein said optional substituents are one tothree R¹⁰ groups; R^(2b) is selected from H and optionally substitutedalkyl, wherein said optional substituents are one to three R¹⁰ groups;R^(2c) and R^(2d) are each independently selected from H and optionallysubstituted alkyl, or together with the nitrogen to which they areattached form an optionally substituted heterocycloalkyl, wherein saidoptional substituents are one to three R¹⁰ groups; at least one of R³,R⁴, R⁵, and R⁶ is selected from OR¹⁴; C(═O)R²²; CH═NR²⁶; NR¹¹C(═O)R²⁰;NR¹¹C(═O)OR¹⁵; OC(═O)R²⁰; OC(═O)NR¹¹R²⁰; O-(alkylene)-R²⁴;Z¹-(alkylene)-R²³, wherein Z¹ is selected from CO₂, O₂C, C(═O), NR¹¹,NR¹¹C(═O), and NR¹¹C(═O)O; and (alkylene)-Z²-(alkylene)-R²³, wherein Z²is selected from O, S(O)_(y), C(═O)NR¹¹, NR¹¹C(═O), NR¹¹C(═O)NR¹¹,OC(═O)NR¹¹, NR¹¹C(═O)O, wherein said alkylene groups are optionallysubstituted with one to three R¹⁰ groups; the other R³, R⁴, R⁵, or R⁶moieties can be selected independently from H, R¹⁰, optionallysubstituted alkyl, optionally substituted alkenyl, and optionallysubstituted alkynyl, wherein said optional substituents are one to threeR¹⁰ groups; Q is selected from an optionally substituted C₁₋₂ alkylene,wherein said optional substituents are one to three R¹⁰ groups; R¹⁰ isselected from alkyl, cycloalkyl, spirocycloalkyl, aryl, heteroaryl,heterocycloalkyl, arylalkoxy, F, Cl, Br, I, CN, CF₃, NR^(27A)R^(27B),NO₂, OR²⁵, OCF₃, ═O, ═NR²⁵, ═N—OR²⁵, ═N—N(R²⁵)₂, OC(═O)R²⁵, OC(═O)NHR¹¹,O—Si(R¹⁶)₄, O-tetrahydropyranyl, ethylene oxide, NR¹⁶C(═O)R²⁵,NR¹⁶CO₂R²⁵, NR¹⁶C(═O)NR^(27A)R^(27B), NHC(═NH)NH₂, NR¹⁶S(O)₂R²⁵,S(O)_(y)R²⁵, CO₂R²⁵, C(═O)NR^(27A)R^(27B), C(═O)R²⁵, CH₂OR²⁵,(CH₂)_(p)OR²⁵, CH═NNR^(27A)R^(27B), CH═NOR²⁵, CH═NR²⁵,CH═NNHCH(N═NH)NH₂, S(═O)₂NR^(27A)R^(27B), P(═O)(OR²⁵)₂, OR¹³, and amonosaccharide wherein each hydroxyl group of the monosaccharide isindependently either unsubstituted or is replaced by H, alkyl,alkylcarbonyloxy, or alkoxy; R¹¹ is selected from H and optionallysubstituted alkyl, wherein said optional substituents are one to threeR¹⁰ groups; R¹² is selected from optionally substituted alkyl,optionally substituted aryl, and optionally substituted heteroaryl,wherein said optional substituents are one to three R¹⁰ groups; R¹³ isthe residue of an amino acid after the removal of the hydroxyl moeityfrom the carboxyl group thereof; R¹⁴ is optionally substitutedheteroaryl, wherein said optional substituents is one to three R¹⁰groups; R¹⁵ is optionally substituted alkyl, wherein said optionalsubstituents is one to three R¹⁰ groups; R¹⁶ is H or alkyl; R¹⁷ isselected from optionally substituted alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl, wherein said optionalsubstituents are one to three R¹⁰ groups; R¹⁸ is selected from H,optionally substituted alkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted cycloalkyl, andoptionally substituted heterocycloalkyl, wherein said optionalsubstituents are one to three R¹⁰ groups; R¹⁹ is selected fromoptionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, and optionally substituted heteroaryl, wherein saidoptional substituents are one to three R¹⁰ groups; R²⁰ is selected fromoptionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, and optionally substitutedheterocycloalkyl, wherein said optional substituents are one to threeR¹⁰ groups; R²¹ is selected from H, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted arylalkyl,optionally substituted heteroaryl, optionally substituted cycloalkyl,and optionally substituted heterocycloalkyl, wherein said optionalsubstituents are one to three R¹⁰ groups; R²² is selected fromoptionally substituted aryl, and optionally substituted heteroaryl,wherein said optional substituents are one to three R¹⁰ groups; R²³ isselected from optionally substituted alkenyl, optionally substitutedalkynyl, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, OR²¹, O(CH₂)_(p)OR²¹, (CH₂)_(p)OR²¹, SR¹⁸, SOR¹⁷,SO₂R¹⁸, CN, N(R²⁰)₂, CHOH(CH₂)_(p)N(R¹¹)₂, C(═O)N(R¹⁸)₂, NR¹⁸C(═O)R¹⁸,NR¹⁸C(═O)N(R¹⁸)₂, C(═NR¹⁸)OR¹⁸, C(R¹²)═NOR¹⁸, NHOR²¹,NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, NHCN, CONR¹⁸OR¹⁸, CO₂R¹⁸, OCOR¹⁷, OC(═O)N(R¹⁸)₂,NR¹⁸C(═O)OR¹⁷, and C(═O)R¹⁸, wherein said optional substituents are oneto three R¹⁰ groups; R²⁴ is selected from optionally substitutedalkenyl, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, optionally substitutedheterocycloalkyl, CN, OR²¹, O(CH₂)_(p)OR²¹, (CH₂)_(p)OR²¹, SR¹⁹, SOR¹⁷,SO₂R¹⁸, N(R¹⁸)₂, CHOH(CH₂)_(p)N(R¹¹)₂, NR¹⁸C(═O)R¹⁸, NR¹⁸C(═O)N(R¹⁸)₂,C(═NR¹⁸)OR¹⁸, NHOR²¹, NR¹⁸C(═NR¹⁸)N(R¹⁸)₂, NHCN, C(═O)N(R¹⁸)₂,C(═O)NR^(27A)R^(27B), C(═O)NR¹¹R²⁸, C(═O)NR¹⁸OR¹⁸, C(═O)NR¹¹N(R¹¹)₂,C(═O)NR¹¹(alkylene)NR^(27A)R^(27B), CO₂R¹⁸, OCOR¹⁷, OC(═O)N(R¹⁸)₂,NR¹⁸C(═O)OR¹⁷, C(═O)NR¹¹R¹⁸ and C(═O)R¹⁸, wherein said optionalsubstituents are one to three R¹⁰ groups; R²⁵ is H, alkyl, aryl,heteroaryl, cycloalkyl, or heterocycloalkyl; R²⁶ is selected fromoptionally substituted cycloalkyl and optionally substitutedheterocycloalkyl, wherein said optional substituents are one to threeR¹⁰ groups; R^(27A) and R^(27B) are each independently selected from Hand alkyl, or together with the nitrogen to which they are attached forman optionally substituted heterocycloalkyl, wherein said optionalsubstituents are selected from alkyl, aryl and heteroaryl; R²⁸ isoptionally substituted arylalkyl, wherein said optional substituent isone to three R¹⁰ groups; p is independently selected from 1, 2, 3, and4; y is independently selected from 0, 1 and 2; and provided that: whenA¹,A² is ═O; B¹, B² are independently H or OH, or B¹, B² combine to form═O; ring A is phenylene; Q is CH—R^(a); and one of R² or R^(a) is H andthe other is optionally substituted

wherein W is optionally substituted C₁ alkyl, or NR^(27A)R^(27B); thenany of R³, R⁴, R⁵, and R⁶ cannot include OR¹⁴ or O-(alkylene)-R²⁴; and astereoisomer or a pharmaceutically acceptable salt form thereof.
 2. Thecompound of claim 1 wherein R² is H, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl, oroptionally substituted cycloalkyl.
 3. The compound of claim 1 wherein atleast one of R³, R⁴, R⁵, and R⁶ is OR¹⁴; C(═O)R²²; NR¹¹C(═O)R²⁰;NR¹¹C(═O)OR¹⁵; OC(═O)R²⁰; or OC(═O)NR¹¹R²⁰.
 4. The compound of claim 1wherein R¹⁴ is benzoxazolyl, benzothiazolyl, pyrimidyl, pyrazinyl ortriazinyl; R²² is a 5-membered heteroaryl group; R²⁰ is heterocycloalkylor heteroaryl; R²³ is heteroaryl or heterocycloalkyl; R²⁴ is heteroaryl;and R²⁶ is heterocycloalkyl, wherein each of said R¹⁴, R²², R²⁰, R²³,R²⁴ and R²⁶ moieties is optionally substituted with 1 to 3 R¹⁰ groups.5. The compound of claim 1 having a structure of Formula II:


6. The compound of claim 5 wherein at least one of R³, R⁴, R⁵, and R⁶ isOR¹⁴, wherein R¹⁴ is benzoxazole, benzothiazole, pyrimidine, pyrazine ortriazine; C(═O)R²², wherein R²² is a 5-membered heteroaryl group;NR¹¹C(═O)R²⁰, wherein R²⁰ is heteroaryl; NR¹¹C(═O)OR¹⁵; OC(═O)R²⁰,wherein R²⁰ is heterocycloalkyl; or OC(═O)NR¹¹R²⁰, wherein R²⁰ iscycloalkyl, wherein each of said R¹⁴, R²², and R²⁰ moieties isoptionally substituted with 1 to 3 R¹⁰ groups.
 7. The compound of claim5 having a structure of Formula III:

wherein ring A is phenylene and R¹ is H or alkyl.
 8. The compound ofclaim 7 having a structure of Formula IV:


9. The compound of claim 7 wherein R² is H, C(═O)R^(2a),C(═O)NR^(2c)R^(2d), SO₂R^(2b), CO₂R^(2b), optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl, oroptionally substituted cycloalkyl.
 10. The compound of claim 7 whereinat least one of R³, R⁴, R⁵, and R⁶ is OR¹⁴, wherein R¹⁴ is benzoxazole,benzothiazole, pyrimidine, pyrazine or triazine; C(═O)R²², wherein R²²is a 5-membered heteroaryl group; NR¹¹C(═O)R²⁰, wherein R²⁰ isheteroaryl; NR¹¹C(═O)OR¹⁵; OC(═O)R²⁰, wherein R²⁰ is heterocycloalkyl;or OC(═O)NR¹¹R²⁰, wherein R²⁰ is cycloalkyl, wherein each of said R¹⁴,R²², and R²⁰ moieties is optionally substituted with 1 to 3 R¹⁰ groups.11. The compound of claim 10 wherein Q is CH₂CH₂ and R² is H oroptionally substituted alkyl.
 12. The compound of claim 1 wherein thecompounds are selected in accordance with the following table:

Ex. No. R³ R² Q R⁵ 1

H CH₂CH₂ OiPr 2

H CH₂CH₂ OiPr 3

H CH₂CH₂ OiPr 4

H CH₂CH₂ OiPr 5

H CH₂CH₂ OiPr 6

CH₂CH₂CH₃ CH₂CH₂ O^(i)Pr 7

H CH₂CH₂ O^(i)Pr 8

CH₂CH₂CH₃ CH₂CH₂ O^(i)Pr 9 H CH₂CH₂OH CH₂CH₂

10 H

CH₂CH₂

11 H CH₂CH₂OH CH₂CH₂

12 H H CH₂CH₂


13. The compound of claim 1 wherein the compounds are selected inaccordance with the following table:

Eg. R³ R² Q R⁵ 136

CH₂CH₂CH₂OH CH₂ H 137

CH₂CH₂CH₂OH CH₂ H 138

CH₂CH₂CH₂OH CH₂ H 139

CH₂CH₂CH₂OH CH₂ H 140

CH₂CH₂CH₂OH CH₂ H 141

CH₂CH₂CH₂OH CH₂ H 142

CH₂CH₂CH₂OH CH₂ H 143

CH₂CH₂CH₂OH CH₂ H 144

CH₂CH₂CH₂OH CH₂ H 145

CH₂CH₂CH₂OH CH₂ H 146

CH₂CH₂CH₂OH CH₂ H 147

H CH₂CH₂ OCH₃ 148

CH₂CH₂OH CH₂ OCH₃ 149

CH₂CH₂OH CH₂CH₂ OCH₃ 150

CH₂CH₂CH₂OH CH₂ H 151

CH₂CH₂CH₂OH CH₂ H 152

H CH₂ H 153

H CH₂ H 154

H CH₂ H 155

H CH₂ H 156

H CH₂ OCH₃ 157

CH₂ H 158

CH₂CH(OH)—CH₃ CH₂ H 159

H CH(OH)CH₃ H 160

CH₂CH₂OH CH₂CH₂ OCH₃ 161

H CH₂CH₂ OiPr 162

CH₂CH₂OH CH₂CH₂ OCH₃ 163

H CH₂CH₂ OCH₃ 164

H CH₂CH₂ OiPr 165

H CH₂CH₂ OiPr 166

H CH₂CH₂ OiPr 167 H CH₂CH₂OH CH₂CH₂

168 H CH₂CH₂OH CH₂CH₂ O(CH₂)₂OH 169 H CH₂CH₂OH CH₂CH₂

170 H CH₂CH₂OH CH₂CH₂ O[(CH₂)₂O]₂Me 171 H CH₂CH₂OH CH₂CH₂

172 H CH₂CH₂OH CH₂CH₂

173 H CH₂CH₂OH CH₂CH₂

174 H CH₂CH₂OH CH₂CH₂

175 H CH₂CH₂OH CH₂CH₂ OCH(CH₃)CO₂Et 176 H CH₂CH₂OH CH₂CH₂

177 H CH₂CH₂OH CH₂CH₂ OCH₂CO₂tBu 178 H H CH₂CH₂

179 H CH₂CH₂OH CH₂CH₂ OCH₂CO₂Et 180 H CH₂CH₂OH CH₂CH₂

181 H CH₂CH₂OH CH₂CH₂ O(CH₂)₂OMe 182 H CH₂CH₂OH CH₂CH₂ O(CH₂)₃CN 183 HCH₂CH₂OH CH₂CH₂ O(CH₂)₅CN 184 H CH₂CH₂OH CH₂CH₂ O(CH₂)₂OEt 185 HCH₂CH₂OH CH₂CH₂ O(CH₂)₄CN 186 H CH₂CH₂OH CH₂CH₂ O(CH₂)₆CN 187 H CH₂CH₂OHCH₂CH₂ OCH₂CN 188 H CH₂CH₂OH CH₂CH₂ O(CH₂)₄C(═NH)OEt 189 H CH₂CH₂OHCH₂CH₂ O(CH₂)₄CO₂H 190 H CH₂CH₂OH CH₂CH₂ O(CH₂)₆CONH₂ 191 H CH₂CO₂Et CH₂OCH₂CO₂Et 192 H H CH₂ OCH₂CO₂Et 193 H H CH₂ OCH₂CN 194 H H CH₂ OCH₂CH₂OH195 H CH₂CH₂OH CH₂ OCH₂CH₂OH 196 H H CH₂ OCH₂CH(OH)CH₂OH 197 H H CH₂OCH₂CONMe₂ 198 H H CH₂ OCH₂CH(OH)CH₂NMe₂ 199 H H CH₂


14. A pharmaceutical composition comprising a compound of claim 1 and atleast one pharmaceutically acceptable excipient.